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Citizens Medals 1-8-01 [Remarks] [David Ho]
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�POTUS
5/25/00
You may be fifth-generation Americans or newcomers to our shores, but you have all enriched our country and
reinforced our values of family, work, and community. We should recognize that, not just in one month but
every day. Thanks to the inventiveness of people like Vinod Dham, we celebrate it whenever we use a
computer with a Pentium chip. We celebrate when we read the works of writers like Amy Tan; when we visit
the haunting Vietnam Memorial; designed by Maya Lin; when we benefit from the path-breaking medical
research of Dr. David Ho; and from countless other Asian-Pacific Americans who are leading us to new
frontiers of science and technology.
6/5/98
Thank you, Dr. Vest. I think you're the real thing. [Laughter] Chairman d'Arbeloff, Dr. Gray, members of the
Corporation, the faculty, especially to the members of the Class of 1998 and your families, the Classes of 1948
and 1973, Mayor Duehay, members of the City Council. I thank the Brass Ensemble for the wonderful music
before. Let me say I am profoundly honored to be here on the same platform with Dr. David Ho, and grateful
for the work he has done for humanity.
�Esquire March 1, 1999
Copyright 1999 Information Access Company,
a Thomson Corporation Company;
ASAP
Copyright 1999 Hearst Corporation. All rights reserved. Further reproduction prohibited.
Esquire
March 1, 1999
SECTION: No. 3, Vol. 131; Pg. 110; ISSN: 0194-9535
IAC-ACC-NO: 54007767
. LENGTH: 5398 words
HEADLINE: PLEASE LEAVE DAVID HO ALONE.
BYLINE: Wilkinson, Alec
BODY:
NOT LONG AGO, THE BRILLIANT DOCTOR HAD AIDS ON THE ROPES, AND THE WORLD TRIED TO
MAKE HIM A CELEBRITY. NOW THE VIRUS COUNTERATTACKS. A LITTLE PEACE AND QUIET, IF YOU
DON'T MIND.
Perhaps no one else named Man of the Year by Time magazine has cared less for the distinction than
David Ho, the AIDS researcher. Ho was Man of the Year for 1996. He felt honored, but he had made
no effort to court the attention of the magazine's editors. What he had done was announce a
treatment that appeared to subdue the virus that causes AIDS. Since the issue for December 30,
1996, was published, with his face behind mirroreq glasses on the cover, he has had to wear a
tuxedo a lot more often than he wishes to, and as many photographs have been taken of him as are
taken of the average person over the course of a lifetime. He has frequently been asked to predict
when the virus that causes AIDS will be defeated, which would make any scientist uncomfortable. He
has spent time that he might have spent in the laboratory explaining his work to reporters, and the
progress of his experiments, which ought to be private, has been breathlessly observed. Ho is the
director of the world's largest private AIDS-research laboratory, the .Aaron Diamond AIDS Research
Center in New York. The center was established in 1990, and Ho is its first director. He was
thirty-seven when he was given the appointment. William Maxwell has written that fame is for young
people who fear being overlooked at parties but that no one in his right mind over forty would ever
wish to be famous. The distraction it creates interferes with serious work.
Aaron Diamond occupies two upper floors in a featureless building on lower First Avenue, ·as if it were
trying to deflect notice from itself. The building belongs to the city. It was built about six dance
crazes ago from steel and glass, and it has a small plaza in front of it. It is the kind of building whose
address you would expect to find on the back of a parking ticket. Its other floors are given over to
agencies involved in public health. People who work in the building carry cards with their
photographs on them. The entrance is guarded by the kind of vigilant and procedure-loving sentinel
who is liable to greet you each morning by your name--Perkins, perhaps, as in "Good morning, Mr;
Perkins"--and then add, "May I see your identification." The center's premises take up the sixth and
seventh floors. They are quiet and tranquil and full of brushed metal and birch paneling and corridors
with double glass windows, behind which men and women in lab coats and masks and rubber gloves
carry out exactly the kind of intricate tasks involving test tubes and slides and probes that show up
in the background on television news shows whenever the stories are about AIDS. The center
employs eighty scientists. A number are Chinese. On the door of one of the laboratories is a small
sign in Chinese characters. The sign asks for luck and was placed there by a scientist who felt vexed
by the results of his experiments.
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�Each Monday morning at 8:30, Ho meets with the twelve men and women who superintend his labs.
All of them are scientists whose reputations are international. They are called staff investigators,
"like detectives," one of them says. They gather on the seventh floor in a conference room with a
long, black, stone-topped table in the shape of a skating rink, surrounded by black leather chairs and
bookcases with bound volumes of publications such as Cell, The Journal of Immunology, Journal of
Virology, and The New England Journal of Medicine. At nine, the staff of the center meets in another
large room on the floor below. Out the window of Ho's office is strange, shabby Bellevue, with its
grim nineteenth-century facade made up of hundreds of small windows like slots with not a sign of
occupation in any of them.
At staff meetings, Ho reads announcements from a legal pad--someone is coming from England to
speak, there's a party for so-and-so on his last day of work--a technician might say something such
as, Some of you have been complaining that some labs are hotter than others, bear with us, we're
working on it. As a rule, someone delivers a talk, perhaps one that he or she has given a few days
before at, say, the nonhuman-primate AIDS conference in Atlanta, and then there are questions. A
visitor might observe of the staff that few of them contribute to the support of Italian designers.
People engaged in making money wear suits--it's an announcement: making money here--whereas
the business on these floors is more dire than simple commerce.
IF YOU THINK OF THE PERSONALITY AS A COLLECTION OF HABITS, gestures, and behaviors
assembled to conceal from other people what we really are thinking, then Ho's personality·is sleek
and sly and efficient. He is generally affable. His expression is attentive and unrevealing. He politely
and resolutely turns aside questions whose answers might disclose how he feels about himself or his
work and accomplishments or his past. He doesn't appear to brood. On his desk there are no piles of
papers, no disarray, no sign of frustration or obstacles, no where-the-hell's-my-pencil?, no
suggestion of an imperious and unstable intelligence opposing a malevolent adversary. Nothing he
does is overtly intended to make people aware of him. No firm has been engaged to see that his
name consistently appears in the. newspapers. Until the middle of last October, requests for him to
speak at a dinner, show up at a ceremony, accept an award, attend a conference, deliver a paper,
assess research, or answer questions from a reporter were disposed of by his younger brother
Sidney, who has since moved to San Francisco to work for a biotechnology company. Ho's office is
large, with dark wood paneling, a big desk, and a smaller table beside a shiny white drawing
board--the kind that coaches use to illustrate plays--for occasions when Ho wants to diagram the
virus. The impression the room conveys is of thought cleanly conceived and executed.
Ho is short and compactly built. His features are youthful. When he leans back in the chair at his
desk, his feet lift from the floor. His walk is not exactly a swagger, but it is confident and determined.
He wears wire-rimmed glasses with lenses about the size of silver dollars. His regard is
straightforward and constant, and the look on his face is slightly beatific. His hair is black and
straight as wire and prone to sticking out slightly above one ear; he sometimes absently pats it while
absorbed in thought. He does not seem to be introspective. One has the feeling that if Ho were to
suffer a devastating professional setback, he would examine it for any illumination and return to
work, devoted to surpassing his former position.
Ho is known to be accomplished at designing experiments so that they are neither overly ambitious
nor flawed by superfluous intentions or incomplete thinking and so that he obtains from them exactly
the findings he needs to support or dismiss his surmises, which are always of consequence. He says
that a scientist must know how to separate the wheat from the chaff. His reasoning is capable of
striking compression. "I'm kind of in awe of him," says Douglas Nixon, a cellular immunologist whom
Ho recruited to Aaron Diamond from Oxford. "His sense of the context of time is acute. We usually
meet only for fifteen minutes or half an hour. Whatever the period, he'll adjust and be totally focused
within that framework, and he'll always end by accomplishing something--an often startling
observation or an answer to a problem. His thinking is that precise."
Nearly any occasion on which Ho accepts an award or makes a speech is a11 opportunity for him to
say he feels that he has been given more than his share of credit. He always mentions that his work
rests on the work of other physicians and scientists. Dr. George Shaw, an investigator at the Howard
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�Hughes Medical Institute at the University of Alabama--that is, a competitor--says about him: "Part
of the wish to do science is the drive to do something creative and entirely new. David is foremost a
.physician. He believes in the Hippocratic oath--First do no harm--and his corollary would be, Try hard
to help. Furthermore, he is a scientist focused on applying the most sophisticated science to the
improvement of human health. He has the compassion and integrity of the best physicians and the
intellect and drive of the best kind of scientist. And it is rare, or at least unusual and gratifying, to
see both in one individual."
The clamor and regard that came from Time's designation might have low-bridged someone more
impressionable, more eager for acclaim, more easily intoxicated by invitations to the White House,
more conventionally ambitious, but Ho has remained absorbed by the intention he embraced nearly
·twenty years ago, when he examined a series of gay men who presented fatal and inexplicable
symptoms, and resolved to discover what afflicted them.
OF THE FIRST FIVE CASES IDENTIFIED AS AIDS, HO MAY HAVE SEEN three. This occurred during
1981. He was completing his residency at Cedars-Sinai Medical Center in Los Angeles, and he was
asked to examine a thirty-year-old patient who had said he was gay. "The man had been feeling
poorly for one or two months," Ho says. "Losing weight, not eating well, and very slowly becoming
short of breath and very fatigued with any form of exertion. Then he really became severely ill, with
intense fevers and shortness of breath--the magnitude was quite shocking. What had precipitated his
hospitalization was a bout of seizures. It was very mysterious. Why should a person who a few
months earlier was healthy crash like that? There was obviously something going on in his
brain--he's having seizures. It's clear from his shortness of breath that he's got pneumonia. Brain
scan shows there's a hole in his brain--that's consistent with seizures and decreased mental status.
And when you biopsy his colon, there's a form of virus causing an infection. It's ubiquitous, this
virus, but should be warded off. The hole in the brain is caused by a parasite. In the lung, there's
another parasite. All of this suggests that something was suppressing his immune system. Was he
using drugs? Certain cancer drugs cause a suppression like that. But he's not in cancer therapy.
"The second patient came about two weeks later. He had an infection in his retina and a mouth full of
yeast--white tongue, thrush. It took a couple of months to get to four, then the frequency increased.
By the end of the first year, we had seen about fifty cases: gay men who came into the hospital with
multiple infections simultaneously, some with pneumonia and brain fever at the same time--what we
would call encephalitis. Very severe headaches along with various neurological complications,
weakness, and sensory abnormalities, perhaps loss of feeling in a leg. The presentations were not
identical, but they were all relating. They were gay men with a high number of partners. A group of
patients with a common thread: infection which would usually be warded off by our immune
systems. Bugs.
"We're used, as doctors, to seeing one problem at a time. It was a premise that there may be
something being passed from one person to another that somehow compromised the immune
system. After a while, there began to be a few cases of heterosexuals, some drug users--at least the
drug users added to the premise that this was transmittable. I'd never heard of a condition like this,
but I said, Let's go back to the literature and see if anything could be found, and there was
absolutely nothing in the textbooks about it. It was scientifically very interesting--something new,
something transmissible, and it destroys the immune system of a previously healthy person.
Everyone thought it was only a medical curiosity; it was labeled as something truly bizarre. I had a
long-standing interest in infectious diseases, and I love puzzles; I was ready to look into certain
diseases which lack explanations--MS had no cause and still doesn't; lupus; rheumatoid
arthritis--and I just decided to make this new disease the focus of my research. Everyone thought I
was crazy, but I decided to chase it. Like everybody else, I never thought it would be what it
became."
IT IS A HALLMARK OF A ROBUST AND PENETRATING MIND TO SEE possibilities in as orderly and
intricate a sequence as if they were dance steps laid out on a floor. The more capable the mind, the
more extensive the pattern. The virus that causes AIDS was identified in 1983, and the next year a
means of testing for its presence was devised. The virus was viewed as indolent, in that it appeared
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�to enter a person and lie dormant for years. Something eventually provoked it; no one knew what. In
the meantime, nothing seemed to be wrong with the patient. No treatment was given.
The virus attacks a component of the immune system called a T cell, specifically a CD4 T cell. A
microliter of blood from someone who is healthy might contain a thousand T cells. When there are
fewer than two hundred, complications occur. Ho noticed that during the period of latency--that is,
when a patient was otherwise thought to be well--he was slowly losing T cells. This suggested (to
Ho) that the virus was engaged, even though everyone else believed that it wasn't.
From the T cell, the virus derives material it uses to replicate itself. An early strategy for subduing
the virus involved offering it artificial decoys. Viruses grown in the laboratory reliably attacked the
decoys. Ho discovered that wild viruses--that is, the ones found in patients--didn't. Since
considerable money had been devoted to this strategy, called soluble CD4, the discovery did not
exactly make Ho popular. The miscalculation regarding the virus led Ho to feel that the virus's
structure was insufficiently understood. It was known that the blood of a patient in the final stages of
AIDS contained huge amounts of the virus. Ho discovered that there were also large amounts in the
blood of a person in the few weeks after he'd been exposed. Around that time, a person usually has a
few days of fever and chills, sore joints, maybe a headache--the symptoms of the flu, although there
is no evidence in his blood of any flu virus. Within a few weeks, the viral load nearly disappears and
in some cases seems to disappear. The person recovers from the fevers and appears to be well.
In 1995, Ho published a paper in Nature, the British journal of science, in which he said that the
virus didn't lie dormant at all. Instead, during the period when it was perceived to be latent, it was
replicating vigorously, and the immune system was just as diligently cleansing it from the body. A
person finally fell sick when his body could no longer keep pace with the implacable industry of the
virus. As with any traumatic experience that becomes prolonged, one person .might hold out longer
than another, but eventually everyone succumbs. As long as the virus was thought to be dormant, it
made sense for doctors to wait until symptoms appeared before they responded. Ho's work
demonstrated that the virus and the body were antagonists from the start and that the best means
of resisting the virus was to attack it immediately.
ANYONE WHO HAS READ HIS PAPER PLACE MAT CAREFULLY IN A Chinese restaurant knows that
Chinese cosmology is cyclical and that each year in a twelve-year cycle is represen~ed by a creature
such as a dog or a tiger or a horse. Ho was born in Taiwan in November of 1952, the Year of the
Dragon. "Many people in China try to have their children in the Year of the Dragon," Ho says.
Children born then are considered to be strong and daring. Ho's given name is Da-i, which does not
translate succinctly into English, although it is often printed as "Great One." Da means "big," and i
means "one." It is an unusual name in China and is derived from Taoism, a Buddhist-inspired
philosophy based on the instructions of Lao-tzu, who embraced simplicity and selflessness. His
father's intention in giving him the name was to imply a being whose capacities were so expansive as
to extend to the edge of the universe, to be so big that they had no outer edge.·
The Hos lived about twenty minutes by bicycle outside Taichung, in central Taiwan. Nearby were rice
paddies and orchards, mostly of guava. Where the orchards stood, there are now apartment
buildings and offices. When David was five, his father took passage on a ship to America with the
plan of settling himself, then sending for the family, which, in addition to David and his mother,
Sonia, included a brother, Phillip, who was two years younger than David. The trip took eighteen
days, and for nearly all of it his father was "sick as a dog," David says.
Eight years passed before the Hos left Taichung. In photographs from the period, David is a small,
fierce presence staring into the camera's lens, rarely smiling, always alert, a kind of sentry. His
mother says that as a small boy he was diffident and held himself aloof from other children. "He just
stood and watched the other kids," she says. "He didn't want to go in and mix it up." In the absence
of his father, he became someone his mother could depend on. She remembers that when he was
five, they went together to a government office to fill out papers so they could eventually emigrate,
and, saying, Don't forget this, and take care of that, he led her through the complicated forms.
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�A Chinese education emphasizes memorization. Children learn to recite works of Chinese literature
and dates in Chinese history. Admission to the best schools comes by means of rigorous tests. Even
when the answer to a question involves an essay, everyone's answers resemble one another's.
Children also attend school in the evening, where they review what they learned during the day. Ho
rode his bike to school along a canal and returned at night in something like complete darkness. He
made his way by steering toward the lights of houses in the distance. When the darkness was
especially forbidding, he pedaled faster. He was an exceptional st'-'dent, but he chafed at the
restrictions and was notable for having an independent cast of mind.
He expected more from himselfthan perhaps was reasonable. His mother says that he came home
from school one day and closed the door to his room and began hitting himself because he had
gotten only a 99 on an exam. A woman doing housework for them came to her and said that she had
better do something or he was going to beat himself to death.
Eventually Ho's father moved to California and became an engineer, but until he did, the family paid
their expenses with a portion of what he earned as a waiter or day laborer. To amuse himself and his
brother, David gave puppet shows, using puppets representing figures from Chinese history. He also
liked to read comic books. Phillip says the comic books mostly concerned superheroes who acted as
defenders of the oppressed. In the fourth grade, David contracted hepatitis and spent several months
at home. He says that he spent half of his time afraid that he would die and the other half worrying
about falling behind at school.
The money the family made from selling their house in 1965 was sufficient to buy three airplane
tickets. "We came to America with six suitcases," Phillip says, "two for each of us--that was our
entire fortune." The only toys he remembers bringing were the puppets. On the way, the boys and
their mother spent one night in Japan. "It was special," says Phillip, "because for the first time we
got to see TV. David and I were glued to it. We both enjoyed samurai movies, and they were on all
the time. And cartoons. Our mother went out shopping, and we stayed at the hotel and watched
movies all night."
When they met their father, they didn't recognize him. He had instructed his wife to speak to them
only in Chinese dialects, because he wanted them to speak English without an accent. Their
American names he got from the Bible. Within a few days, David had gone from being the brightest
boy at school to not understanding what anyone was saying. "Every day he came home from school,"
says his mother, "I asked him how did it go, and he would say, 'I can't understand what they are
saying; they tell me I am stupid.' "His confidence faltered. He became withdrawn. His father insisted
to the school that David be placed in a class for gifted students. The school thought he should be in
special education. The one class in which he excelled was mathematics. He and Phillip relied on each
other for companionship. They watched a lot of television, mostly the Three Stooges. "When you
don't understand the language," Phillip says, "slapstick is universal. Mainly we walked around with
dictionaries."
Ho applied himself as diligently as he always had. "At night, I would get up sometimes," says his
mother, "and see his light is on. He was still studying at two in the morning, and I would knock on
his door and say, 'You have to go to school in the morning,' and he would say, 'Leave me alone, I
know what I'm doing.' Whatever level everyone else does, he would try to do one better." It took
about a year for him to become comfortable with English. He believed that because he was Chinese
and not white, he would have to work harder to protect himself from being discriminated against.
The Hos attended a small church in Glendale whose congregation included David Henry Hwang, who
wrote M. Butterfly. "The church was very young," Hwang says. "First Evangelical Church of Glendale.
My uncle was the pastor. It's what would be considered these days a born-again church. There were
only four children in the Sunday school. I remember that David was always very considered. What I
mean is, the environment didn't encourage thinking, but he did. He was able to remain open-minded
in a context that didn't support it."
When the Hos had a third child, a boy, they allowed David and·Phillip to name him. The brothers
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�chose Sidney, after a character in a movie starring Jerry Lewis.
Ho went to MIT for a year, then transferred to the California Institute of Technology to study physics
and become, like his father, an engineer. He grew aware that the best prizes in science went to men
and women in medicine, especially to scientists engaged in molecular biology and gene splicing. He
decided to go to medical schoo.l and was accepted at Harvard.
If you happen to be the sort of person interested in the workings of the unconsCious mind, you might
have noted a pattern in Ho's life: From the time when he was five until he was thirteen, he lived in
Taiwan without his father. He says about his father's departure, "I remember him leaving, but I don't
remember what I felt about it." Durir)g the following days, there was always on the horizon an event,
maybe only dimly or intermittently perceived: the approach of the day when he and his brother and
his mother would leave for America, where they wouldn't understand what people were saying,
where he would shed his familiar identity for one that was uncertain. That is, during a period when
his life was advancing according to the pattern of childhood, another influence, perhaps unsuspected
and unsettling, was at work beneath the passing of his days.
Years later, he takes up the examination of a disease that is universally acknowledged to display a
specific pattern of attack: a signal event--the act of infection, perhaps overlooked--followed by a
period of dormancy equaling something like eight years, which concludes with an abrupt shock, the
arrival of symptoms, and the departure into an uncertain future. Relying heavily on intuition, Ho
discovers that during the time when nothing appeared to be happening on the surface of a tranquil
life, other influences, unsuspected and insistent, were raging.
AZT, THE FIRST DRUG TO SUCCESSFULLY IMPEDE THE VIRUS, affected the virus's ability to
replicate, but the virus needed sometimes as little as a few days to evolve into resistant forms. In
1991, at a conference outside Orlando, Ho met a bench chemist named Dale Kempf, who worked for
Abbott Laboratories in Chicago. Ho was at the conference· to deliver a talk, and Kempf had been
invited to give a poster presentation--that is, to display his work on a series of posters and stand·
beside it and answer questions. Kempf had been developing drugs called protease inhibitors. A
protease enzyme is an enzyme that the virus uses to replicate. "What it is," Ho says, "is a chemical
scissors: The viral protease cuts the viral protein from big pieces into smaller pieces; the smaller
pieces aggregate to form the viral particle." Ho felt that if you "gum up the scissors," you might
interrupt the virus. Ho and Kempf found themselves standing together in line to return their rental
cars. "We started to chat," Ho says, "developed a friendship, and decided that we would complement
each other--he's a chemist; he doesn't work with the virus. He made the drugs. We talked about how
the virus might develop a strategy to evade the drugs."
The virus replicates furiously. As it happens, it is notably prone to error. Each time it copies itself, it ·
makes mistakes--an advantage, since the immune system must constantly respond to an altered
adversary. "We're 99 percent the same as chimpanzees," Ho says, "and look how long it has taken
us to evolve that 1 percent. The virus changes 1 percent a year. The immune system is trying to
chase after this."
To address the virus's plastic qualities, Ho and others borrowed a strategy from cancer therapy.
Rather than employ a single drug and perhaps allow some portion of the virus to become resistant,
they began using several drugs, hoping to overwhelm it. These combinations, which include a
protease inhibitor, are described as drug cocktails. "We know how fast the virus is replicating," Ho
says, "and how fast it will generate the mutants. If I ask it to make one mutation, it can probably do
that fairly quickly. Even if I ask it to make two. I'm going to ask it to make five mutations at the
same time, and that is numerically very, very unlikely. You create so many fronts for it to fight. This
is the chess game we play with the virus."
The drug cocktails worked so well that in many patients the amount of virus in their bloodstream
dropped below levels that could be detected. No longer under constant attack, their immune systems
revived and addressed the bacterial and fungal infections besetting them. The patients got better.
The calculations of a mathematician Ho consulted suggested that the drugs would cleanse the body
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�of any trace of the virus within two to three years. Tests in animals suggested that if a person began
taking the cocktails within, say, two days of being infected, he might defeat the virus completely. At
the very least, a disease that was incorrigibly fatal appeared to have been subdued. Ho became Man
of the Year.
THE PERIPHERAL EFFECTS OF protease inhibitors, it turns out, are severe. They cause cramps and
gastrointestinal distress, and they undermine the liver. They interfere with the body's capacity to
metabolize fat; patients develop what are called protease paunches and buffalo humps--complaints .
doctors originally dismissed as being only a matter of vanity, until they discovered that the fat can
give rise to .diabetes and heart disease.
In addition, patients sometimes make mistakes in following the rigorous schedule for taking the
medications, and any lapse works in favor of the virus. Some patients say that the drugs cause more
problems than they solve and give them up. When they stop, the virus returns. A patient taking the
drug cocktails might return to sufficient health that his immune system will overcome the remaining
virus. Some portion of the virus, though, remains latent in T cells, where it has been incorporated
into the cells' DNA and is difficult to evict. Ho initially thought that such cells didn't live long enough
to provide the virus much shelter but has since learned that some can live twenty or thirty years.
These cells might become active only if called on to oppose an infection--the flu, say. To purge the
virus hidden in such strongholds, Ho believes that the cell has to be awakened, which could be done
by intentionally making a person sick. The cells Would perform, and the virus would emerge and be
subdued by the ingredients of the cocktail. What concerns him is that the virus might find sanctuary
in sites such as the brain, an organ that antiviral drugs are not especially adept at reaching. Also,
there is some question of how long a person can sustain the drug therapy. Last summer, a young
man undergoing drug-cocktail therapy in Washington, D. C., suffered a heart attack brought on by
difficulties caused by the accumulation of fat.
Ho did not expect he could save everyone. He knew that the use of protease inhibitors would involve
complications--all drugs do; exactly what the complications would be, and how severe, he continues
to learn. Even so, he points out that since they were put into use three years ago, the death rate
from AIDS in America is a fifth of what it was. How long these numbers will hold, no one is sure. He
still refines their ingredients.
The rest of his time he spends trying to better understand the virus's structure and working toward a
vaccine and a cure. If someone else discovers a cure, he will work .on a vaccine. If someone else
discovers a vaccine, he will work on a cure. If he figures in neither of these discoveries, he will
devote himself to seeing that they are distributed, especially in Asia and Africa, where the people
who need them are not likely to be able to afford them. In the minds of many people, protease
inhibitors have been viewed not as a means of thwarting the virus, but as a cure, even though Ho
has been careful to say that they're not. The misconception has made the discourse on AIDS in
America less fervent, which pains him.
I READ THAT HO IS FOND OF A TAOIST SAYING, "The softest things in the world overcome the
hardest thi"ngs." Sitting in his office one day, I asked if he was religious, and he said, "Not really."
Because he is smarter than I am, I had hoped to hear an explanation of how he views God's presence
in a world that includes an adversary as merciless as the one he knows intimately. I asked if he ever
viewed the world in terms of such a design, and he said, "Not at all. This universe doesn't exist just
for us. We're only one of millions of species, each evolving to become better and better. This virus's
strategies are very simple: We are a food source for this virus."
I·
That evening, I went with Ho and his wife and their son and younger daughter to a dinner at a hotel
in midtown Manhattan, where he was one of several people being honored. The dinner was given by
an organization called the Asian and Pacific Islander Coalition on HIV/AIDS. Ho was receiving its
Genius award. We drove up from his office in his car, which he parked on a street where parking
would not be legal for another hour, but which was already parked up anyway. I asked if he had a
DOCTOR ON CALL sign to put in his window. "No," he said. "Besides, if you do that, they break into
your car for the drugs." I said, "Yeah, but it's a Mercedes--they'll break into it anyway." And he said,
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�cheerfully, "That's all right--there's a Lexus behind it."
In a low-ceilinged room outside the hotel's ballroom, men in tuxedos and suits and women in long
dresses were waiting for him. Reporters and photographers from Asian papers walked around with
cards on their lapels that read, PRESS. A trio played cocktail music in a corner. After the dinner
plates had been cleared, Ho would accept a piece of ceramic sculpture. He would say, "More credit
than I deserve ... work of other scientists ... much remains to be done." First, though, he would
stand at the entrance to the room and say, "It's going to get hectic." Then he would step into the
room. A photographer would approach and say, "David, may I get a shot of you with your family?"
and he would stand in a corner, beside his wife and son and daughter, and smile, his eyes closed, the
flash-bulbs from the cameras lighting up the room like detonations.
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8 of8
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�- heaaune ~aavm nuJ
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Time, December 30, 1996
Copyright 1996 Time Inc.
Time
December 30, 1996
SECTION: SPECIAL DOUBLE ISSUE/MAN OF THE YEAR; MAN OF THE YEAR; Pg. 56
LENGTH: 4401 words
HEADLINE: THE DISEASE DETECTIVE;
AS THE AIDS EPIDEMIC UNFOLDED, DR. DAVID HO HAD A KNACK FOR ASKING JUST THE RIGHT
QUESTIONS
BYLINE: CHRISTINE GORMAN, REPORTED BY ALICE PARK/NEW YORK AND DICK THOMPSON/
WASHINGTON
BODY:
Dr. David Ho doesn't look like a gambler. With his boyish face and slender build, he could more
easily pass for a teenager than for a 44-year-old father of three--or, for that matter, for a
world-renowned scientist. In fact, when he was an undergraduate at the California Institute of
'Technology back in the 1970s, Ho hung around the blackjack tables in Las Vegas, tilting the odds in
his favor by memorizing each card as it was played. He got so good at counting cards that he was
thrown out of several casinos.
Today Ho is still something of a gambler, though in a very different field and for much bigger stakes.
The director of the Aaron Diamond AIDS Research Center in New York City, he has come up with a
daring strategy for flushing out the virus that causes AIDS. As he explained at the 11th International
Conference on AIDS in Vancouver, Canada, last summer, Ho (like more and more doctors) is using
powerful new drugs called protease inhibitors in combination with standard antiviral medications. But
unlike most doctors, he gives the so-called combination therapy to patients in the first few weeks of
infection.
Already the HIV in his patients' blood has dropped so low it can no longer be measured. Because he
is attacking early and not waiting for full-fledged AIDS to develop, Ho told the conference, there is a
good chance that within two or three years the virus could be completely eliminated.
Eliminated. Just a few months ago, no one in the AIDS community and no reputable scientist would
presume to imagine such a thing. Journalists, activists and researchers peppered Ho with questions
at the podium. Had he found the cure? Could people stop worrying about AIDS? Could they throw
away their condoms? .
No, no and no. What he had done, Ho explained, was begin an experiment that might, under the
right circumstances, eliminate the virus from a small group of men caught within three months of
infection. He couldn't offer the same hope to the estimated 100,000 patients in later stages of
infection who in the past year have begun taking the same antiviral "cocktails"--often with
encouraging results--but whose AIDS is probably too far advanced for them to expect a long-term
recovery.
Like so many promising HIV treatments, Ho's strategy could fail. It could even backfire if it is
mistakenly touted as a kind of "morning after" treatment that allows people to relax their guard and
engage in risky sexual behavior. By desensitizing the virus to medications, it could jeopardize a
patient's ability to respond to future treatments. Worse yet, it could inadvertently create a mutant
strain of virus resistant to all currently available drugs--a kind of super HIV--that could lead to a
1 of8
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�second, even more devastating AIDS epidemic.
There are other problems. Even if the treatment works, it isn't practical. HIV-positive patients would
have to start taking the drugs immediately after infection, before they realize they're sick. And even
if the drug cocktails can be made to work in the later stages of infection, they are far too expensive
to do much good for the 20 million people in the developing world who are infected with HIV. In the
long run, scientists believe, only an AIDS vaccine will stop the global epidemic.
Still, it's easy to understand the tentative sense of hope and excitement that has spread across the
AIDS community in the months since the Vancouver conference. Ho's speech, for all its caveats,
provided the first concrete evidence that HIV is not insurmountable. After 15 years of horror, denial
and disappointment, the pendulum may at long last be swinging against AIDS.
A TEAM EFFORT
David Ho would be the first to say that he cannot take all the credit. It was an immunologist from
Los Angeles named Michael Gottlieb who in 1981 reported the first cases of what was then called gay
pneumonia. It was the U.S. Centers for Disease Control that alerted doctors to the gathering
epidemic and established that the. infection was transmitted through blood transfusions, tainted
needles and unprotected sex. It was Dr. Luc Montagnier's laboratory at the Pasteur Institute in Paris
that first isolated the killer virus in 1983. It was Dr. Robert Gallo and his colleagues at the National
Cancer Institute in Bethesda, Maryland, who made it grow in the lab, which allowed for the
development of an antibody test. It was the National Institutes of Health that funded the basic
research on HIV and AIDS. It was the big drug companies like Burroughs Wellcome and Merck that
brought a growing list of anti-HIV drugs to market.
But Ho, working alone or in concert with others, fundamentally changed the way scientists looked at
the AIDS virus. His breakthrough work in virology, beginning in the mid-1980s, revealed how HIV
mounts its attack. His tenacious pursuit of the virus in the first weeks of infection helped show what
the body does right in controlling HIV. His pioneering experiments with protease inhibitors helped
clarify how the virus ultimately overwhelms the immune system. His work and his insights set the
stage for an enormously productive shift in the treatment of AIDS away from the later stages of
illness to the critical early days of infection.
Once, not so long ago, researchers believed that nothing much happened after HIV gained entry into
the body. The virus simply hunkered down inside a few of the immune system's T cells--the linchpins
of the body's defensive forces--for anywhere from three to 10 years. Then something, no one knew
what, spurred the microbial invader to awaken. In this picture, the AIDS virus spent most of its life
hibernating before starting its final, deadly assault.
In the past two years, Ho and his colleagues have demonstrated that this picture of the virus is
wrong. There is no initial dormant phase of infection. Ho showed that the body and the virus are, in
fact, locked in a pitched battle from the very beginning. At first many AIDS researchers found this
hard to accept; it challenged some of their most cherished assumptions. If Ho was right, doctors
would have to radically alter the way they treated AIDS.
It wasn't the first time that Ho had overturned conventional wisdom. During the past 15 years, he
has demonstrated an uncanny ability to ask questions that seem obvious only in retrospect and to
probe key issues others have overlooked. It's a trait that does not endear him to some of his rivals. A
few have accused Ho of being a publicity seeker who is giving AIDS patients false hope. Upon
examination, however, most of the accusations appear to spring from professional jealousy. "David is
the type of individual whom I feel particularly good about when he achieves success," says Dr.
George Shaw, one of Ho's strongest competitors, who runs a state-of-the-art AIDS research
laboratory at the University of Alabama in Birmingham. "He is a stellar scientist."
Ho has an extraordinary knack for being in the right place at the right time. Two years after he
received his M.D. from Harvard Medical School, Ho witnessed the birth of the AIDS epidemic. He
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�_ ........ - ..• ~ ~"'""'~'"vuu rcscarcntremeve·!_ ...WV &_mds=:::-sc66c63dS79b26a961699s~aec28tb!
remembers how baffling it seemed.
The year was 1981, and Ho was chief medical resident at Cedars Sinai Hospital in Los Angeles.
Across town at UCLA, Gottlieb had identified a new syndrome that seemed to target gay men. E~ch
of the cases was different, but all had one thing in common: whatever was making the men sick had
singled out the T cells for destruction. Eventually the body's battered defenses _couldn't shake off
even the most innocuous microbial intruder. The men were dying from what doctors termed
opportunistic infections, such as Pneumocystis pneumonia, which attacks the lungs, and
toxoplasmosis, which often ravages the brain.
Ho began seeing more and rriore of these patients in the intensive-care units at Cedars Sinai. Some
doctors thought that poppers and other recreational drugs triggered the immune collapse. Others
believed it was a bizarre allergic reaction from having too many sex partners. But Ho fell into the
camp that suspected a virus. He quickly decided to specialize in AIDS research. "David was clearly a
big thinker even then," says Dr. Mark Ault, who was a resident at Cedars Sinai at the time. "But that
didn't stop us from kidding him about how he was always looking for gay men."
Ho ignored the gibes and in 1982 landed in Martin Hirsch's virology laboratory at Massachusetts
General Hospital in Boston. A prominent scientist in his own right, Hirsch is known for cultivating
talented young researchers.
Like many other ambitious young scientists, Ho wanted to be the first to isolate the virus that causes
AIDS. Luc Montagnier and Robert Gallo beat him to it. (Ho came in fourth, after Jay Levy of the
University of California, San Francisco.) Still, while working in Hirsch's lab, Ho became expert at
detecting HIV in places where few were able to find it. He was the ffrst to show that it grows in
long:-lived immune cells called macrophages and among the first to isolate it in the nervous system
and semen. Just as important, he showed that there isn't enough active virus in saliva for kissing to
transmit the infection. "David had the Midas touch," Hirsch recalls. "Whatever he did worked."
Unfortunately, Hirsch was not Midas, and he couldn't afford to pay his postdocs more than the
standard$ 18,000 yearly stipend. To support his family, Ho started moonlighting in Mass General's
walk-in clinics. It turned out to be the right time to be in that place too. "The clinics are where you
see the flus, the colds, the common illnesses," Ho says. In the mid-1980s, however, he started
seeing gay men with what appeared to be an unusually severe flu. They always got over their illness
without any of the hallmarks of AIDS. Still, he wondered, could there be a connection? Could these
flu-like ailments be the signs of the men's very first exposure to_HIV?
Sure enough, blood tests showed that the "flu" corresponded with the sudden appearance of
HIV--and the total absence of any influenza viruses. Then, after a few weeks, the antibodies in the
immune system would jump sharply while HIV disappeared from the circulation. It was the first
evidence that HIV triggered an active infection. But not even Ho would recognize its significance until
years later.
LEARNING FROM FAILURE
Despite rising casualties, Washington kept tight purse strings on func!ing for AIDS research for much
of the 1980s. By 1987, though, even Ronald Reagan knew that AIDS was a serious threat. The
plague had encircled the globe, stretching from Africa to Asia. The antibody test revealed the
presence of HIV in the blood supplies of the U.S., France and Japan. The FDA approved use of the
antiviral drug AZT in a record 14 weeks.
At that time, scientists across the U.S. were excited about a possible breakthrough treatment:
soluble CD4. They knew that HIV does not infect T cells at random. It must first attach itself to a
particular protein, called CD4, on the T cells' surface. Perhaps, researchers reasoned, if they flooded
the bloodstream with free-floating CD4 molecules, the molecules would act as decoys and prevent
HIV from infecting the T cells. Preliminary tests on viral samples grown under laboratory conditions
showed that soluble CD4 worked beautifully.
'.of8
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�Ho had taken a junior faculty position at UCLA and moved his family back to California. He contacted
Dr. Robert Schooley of the University of Colorado Medical Center in Denver, and together they
embarked on a clinical trial of soluble CD4 in two dozen patients, many of them in the later stages of
AIDS. Unfortunately, Ho and Schooley wound up proving that soluble CD4 doesn't work. In the
process, however, they discovered something very interesting--that there were tens of thousands of
infectious viral particles in their patients' bodies, a lot more than anyone had expected.
It took Ho only a few weeks to figure out why soluble CD4 didn't work. The early tests on the
treatment were done on weak strains of virus grown in the lab. Somehow wild viruses could tell
which CD4 molecules were decoys~ Ho and the rest of the AIDS scientists had just learned a valuable
lesson. They would have to test all their potential treatments on viruses that infected real patients.
BACK TO BASICS
The experience with soluble CD4 showed Ho that therewere significant gaps in science's
understc;mding of the life cycle of HIV. He decided to revisit his earlier Boston work on the first stages
of infection. By hanging out in hospital emergency rooms and talking to colleagues, he and his team
at UCLA identified four young homosexual men suffering from the flu-like symptoms of a primary HIV
infection. Ho used a newly available tool of genetic engineering--the PCR test used most famously in
the O.J. Simpson trial--to measure the amount of virus in the blood. Once again, he was astonished.
By this time, most researchers agreed that people in the later stages of AIDS had large quantities of
HIV in their blood. But the PCR test showed that millions of viral particles were coursing through
Ho's patients' blood in the earliest weeks of infection as well--as many as could be found in someone
with a full-fledged case of AIDS. Within a few weeks, the viral load plunged to low and in some cases
undetectable levels. The patients recovered and seemed healthy.
Ho wasn't the only scientist who had observed this. Another team, headed by George Shaw, had
seen the same spike in HIV particles followed by a precipitous drop. The two researchers learned of
each other's work and decided to co-publish their findings in a 1991 issue of the New England
Journal of Medicine. It was the beginning of a friendly but no less keen competition between the
scientists.
It was also the beginning of a new phase in Ho's career. Philanthropist Irene Diamond had decided
to found an AIDS research center in New York City and had chosen Ho as its director. He was 37
years old. "I took a bit of flak because everybody said, 'He's so young, he's unknown."' she recalls. "I
said, 'I don't want a star, I want a wonderful scientist."' For his part, Ho considered the benefits of
having more lab space and secure financial backing. "It was still a risky venture," he remembers.
"Marty Hirsch said, 'You're crazy. This is New York City. The politics will eat you up."' But for Ho, the
chance to do what he wanted, and to attract top-level scientists to join him, was too good to pass up.
Ho and Shaw had proved that there are high levels of virus in the first few weeks of infection. Ho
and Schooley had already shown that there is a lot more virus in the end stages of AIDS than anyone
had thought possible. The next question was obvious: What is going on during those middle years,
when patients are still in relatively good health? Ho suspected that the answer could dramatically
change the way doctors treated their HIV-positive patients.
All the blood tests indicated that the viral load was close to zero throughout the middle years, though
it would gradually increase as time went by. Both Ho and Shaw realized, however, that zero doesn't
always equal zero in the world of HIV. For one thing, the virus might be hiding out in the lymph
nodes, where it could be producing thousands or even millions of copies of itself every day. As long
as the immune system cleared those infectious particles as quickly as they formed, blood tests would
show no change in viral load. "It's like a person running on a treadmill," Ho explains. It doesn't
matter how fast they run. To an observer, they appear to be staying in place.
4 of8
1/3/2001 11:06 AM ;
!
�Not even the greatest marathoner could keep up that pace forever. If the virus reproduced very
quickly, it would eventually exhaust the body's defenses. At least that's what Ho and Shaw thought.
The trick to proving their idea was to find some way to suddenly stop the treadmill. If you did that to
a jogger, he would lurch forward. Similarly, if you stopped HIV's cycle of reproduction in the blood,
the immune system should suddenly rebound. By measuring that rebound, the scientists hoped to
figure out just how rapidly the virus had been reproducing.
Great idea, in theory. There was just one problem: no one knew how to stop HIV that quickly. AZT
wasn't powerful enough to do it. The pharmaceutical companies, however, had just started looking at
a new class of substances, called protease inhibitors, that might fit the bill. As it turned out, it took
several years of testing to come up with a formula for a protease inhibitor that was effective against
HIV.
REINFORCEMENTS
The year was 1994, and the new drugs were finally producing good results in the test tube. They
worked against laboratory strains of the virus; they worked against viral samples taken from
patients. Where AZT merely slowed viral reproduction, the protease inhibitors shut it down almost
completely. Unfortunately, almost wasn't good enough. It often took less than a month for a few viral
particles to mutate into a strain that was resistant to protease inhibitors. The new drugs were
starting to look like another failure.
But a few weeks was all that Ho and Shaw needed to conduct their rebound experiments. The two
laboratories raced to find the answer.
·
Ho chose 20 volunteers whose T cells had dropped from a normal level of about 1,000 cells per ml of
blood to fewer than 500. The newest PCR tests showed that the viral load of these patients was
holding steady at about 100,000 copies per ml of blood. Ho started treating his subjects with one of
the new protease inhibitors being developed by Abbott Laboratories. As expected, the amount of
virus that could be measured in the patients' blood practically disappeared. The treadmill had been
stopped. But no one was ready for what happened next.
Preliminary calculations indicated that the immune system was rebounding faster than anyone had
thought possible. The results showed that in every day of every year, in every infected person, HIV
produced not thousands, not millions, but billions of copies of itself. And every day the body
launched billions of immune cells to counter the threat. The wonder was not that the immune system
eventually crashed. Given such intense fighting and heavy casualties, the wonder was that it lasted
so long. Ho and Shaw came up with the answer at the same time and published their results in
back-to-back articles in a 1995 issue of Nature.
Suddenly the entire picture of AIDS had changed. As long as doctors thought that the virus was not
very active through the early and middle years of infection, it made sense to conserve forces and
delay treatment so they would be ready for the virus when it emerged from hibernation. Now it was
becoming clear that the immune system needed all the help it could get right from the start.
But where would that help come from? Boston's Martin Hirsch and other virologists had already
started looking to cancer research for inspiration. Oncologists have learned that it is often better to
combine the firepower of several different chemotherapeutic drugs than to rely on any single
medication to destroy cancer cells. Too often, they have found, the one-drug approach allows a few
malignant cells to survive and blossom into an even more lethal tumor. The AIDS researchers faced a
similar problem with HIV. Whenever they prescribed a single drug, such as AZT, for their patients, a
few viral particles would survive and give rise to drug-resistant HIV.
Now that the protease inhibitors had become available, ·doctors were eager to combine them with the
old standby AZT and a third drug called 3TC. A couple of mathematical models--created by one of
Ho's collaborators, Alan Perelson of the Los Alamos National Laboratory--suggested that HIV would
have a hard time simultaneously undergoing the minimum three mutations necessary to resist
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�combination therapy. He placed the odds at 10 million to 1. It was at least worth a try.
HOPE AT LAST
For once in the history of HIV, a strategy that ought to work seemed in fact to succeed. Within weeks
of starting combination therapy, 7 out of 10 men and women with AIDS begin to get better. Blood
tests show that in many of them, the viral load has dropped below detectable levels. Relieved of the
burden of fighting HIV, their long-suffering immune systems can finally tackle the deadly fungal and
bacterial infections that have taken hold in their lungs, intestines and brains. Fevers break; lesions
disappear; energy returns.
'
'
With the virus under control in at least some AIDS patients, doctors are considering how to rebuild
their battered immune systems. After a decade of fighting HIV, many of the body's defensive
reserves have been thoroughly depleted and cannot be regenerated from within. Researchers plan to
grow replacement cells in the laboratory for transplant into recovering patients. Before the advent of
combination therapy, no one would have considered such a rescue effort because the unchecked
virus would have rapidly destroyed the new implants.
It all sounds so hopeful. Why don't scientists say at the very least that they're close to the cure? For
the same reason that Ho did not promise the crowd in Vancouver that he could eliminate HIV from
people in the later stages of the infection. Researchers know that after years of infection, there isn't
a hiding place in the body that the virus hasn't penetrated. A cure must do much more than clear
HIV from the bloodstream. It must remove the virus from the lymph nodes, the brain, the spinal
fluid, the male's testes and everywhere else it may be hiding. Today's combination therapies work in
the blood, but they don't reach into the brain or the testes very well.
Chances are that people in the later stages of the disease will have to stay on combination therapy
the rest of their lives--assuming they can tolerate the often excruciating side effects, which range
from diarrhea and fatigue to spasms, kidney stones and liver damage. They also have to bear in
mind that they are probably still infectious and that eventually--perhaps in a few years, perhaps
longer--their immune systems will probably once again collapse.
But what if you could avoid all those problems, Ho wondered. What if you didn't wait until the end
stages of the disease but started combination therapy during the first few weeks of the infection,
before too many billion viral particles had formed, before resistance became inevitable, before too
many billion immune cells had died in the body's defense? Would you have tilted the odds enough in
the immune system so that it could wipe out whatever stragglers might be left, wherever they were
hiding?
To find out, Ho and one of his team, Dr. Martin Markowitz, recruited two dozen men in the earliest
stages of infection and placed them on combination therapy. All the men appeared healthy before
treatment. For them, ironically, the first signs of illness have been the side effects of the drugs they
are taking, not the virus. Three have dropped out because they couldn't take the nausea and
cramping.
Some of the men have been treated for more than a year. None of them show any trace of HIV in
any of their blood. Ho has not forgotten, however, that zero does not always equal zero. He and
Markowitz are looking for pockets of virus in the lymph tissue, the semen and the spinal flu.id.
Ho believes that prospects for success are good. Assuming that nothing has been overlooked,
combination therapy should burn the virus out of the body in two to three years, according to
Perelson's latest mathematical models. Because treatment began so early, the men's immune
systems should be able to replace any lost defensive cells. There is still a chance that bits of the
virus, called proviral dna, are lodged in the chromosomes, beyond the reach of even the most
powerful drugs. Ho has studied these vestigial snippets of genetic information and believes they are
defective and cannot give rise to a new generation of HIV. Other scientists are not so sure. The only
. way to find out is to stop the medication and see if the virus comes back.
) of8
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�None of Ho's patients plan to take that step anytime soon. And he doesn't blame them. Just a few
surviving viruses could manufacture enough copies to resaturate a body in a matter of days, forcing
the patient to start the long treatment process all over again. But at least one of Ho's patients has
agreed to stop taking his drugs in another year or two--after his doctors assure him that tests show
no evidence of HIV in his lymph, semen, spinal fluid or elsewhere in his body. When he does, we will
know, probably within a few weeks, whether the virus has returned or whether it is gone for good.
Even if the virus stages a comeback, that doesn't necessarily mean that combination therapy has
totally failed. It may be that additional ingredients could eliminate the virus completely. Ho has
already started using a combination of four drugs in another early-intervention trial. And he has
access to new, experimental medications that can better penetrate the brain and perhaps the testes.
These drugs may help patients in later stages of the disease whose infections have become resistant
to current treatments.
There is still a long way to go, both in the quest for an effective treatment and in the search for a
way to prevent infection in the first place. In the flush of the new optimism, some scientists are more
hopeful about the prospects for gene therapy, which could possibly make the immune system
impervious to HIV attack. Another promising line of research centers on a group of molecules called
chemokines, which may one day be used to shield cells from HIV. Other scientists, including Ho, are
intensifying their search for a vaccine. Two weeks ago, the nih increased its budget for AIDS-vaccine
research 18%--to $ 129 million--and named Nobel-prizewinning molecular biologist David Baltimore
to head the effort.
·It has taken the collaborative work of thousands of scientists and physicians to get this far. It will
take even greater cooperation and well-funded coordination to overcome the remaining hurdles. But
the worst fear--the one that seeded a decade with despair, the foreboding sense that the AIDS virus
· might be invincible-~has finally been subdued.
--Reported by Alice. Park/New York and Dick Thompson/Washington
For more information, visit our Man of the Year Website at time.com/moy
GRAPHIC: COLOR PHOTO: PHOTOGRAPH FOR TIME BY GREGORY HEISLER. SCANNING, ELECTRON
MICROGRAPH FROM NIBSC/SPL--PHOTO RESEARCHERS, COVER, MAN OF THE YEAR, DR. DAVID HO,
AIDS RESEARCHER, [David Ho looking at enlarged image of a T cell infected with AIDS virus, which
is reflected in his glasses]; COLOR PHOTO: GREG GIRARD--CONTACT FOR TIME, [David Ho--T of C];
COLOR PHOTO: PHOTOGRAPH FOR TIME BY GREGORY HEISLER, ON THE CASE, Ho in his
headquarters at the Aaron Diamond AIDS Research Center in New York City [David Ho]; COLOR
PHOTO: INSTITUT PASTEUR--CNRI/SPL/PHOTO RESEARCHERS, [Magnified image of retrovirus];
COLOR ILLUSTRATION: TIME DIAGRAM BY JOE LERTOLA, [Diagram illustrating life cycle of the AIDS
virus and how it might be stopped]; COLOR PHOTO: MCINTYRE--PHOTO RESEARCHERS, [Bag of
blood]; COLOR PHOTO: DENNIS BRACK--BLACK STAR~ [Bottles in laboratory]; COLOR PHOTO: ALLAN
TANNENBAUM--SYGMA, [Luc Montagnier and another man]; COLOR PHOTO: J.J. BERNIER--GAMMA
LIAISON, [Rock Hudson]; COLOR PHOTO: JOHN SEAKWOOD--OUTLINE, [C. Everett Koop]; TWO
COLOR PHOTOS: DENNIS BRACK--BLACK STAR (2), [Bottles of AZT; Liberace]; COLOR PHOTO:
FRANK FOURNIER--CONTACT/THE STOCK MARKET, [AIDS protestors]; B/W PHOTO: CBS NEWS/60
MINUTES, [Gaetan Dugas]; COLOR PHOTO, [Box and bottle of AIDS drugs]; COLOR PHOTO: ALEN
MACWEENEY--OUTLINE, [Keith Haring]; COLOR PHOTO: MARY ANN CARTER--SIPA, [Ryan White];
COLOR PHOTO: HBO--ZUMA, [Arthur Ashe]; COLOR PHOTO: TED SOQUI--IMPACT VISUALS, [Magic
Johnson]; COLOR PHOTO: JACK MITCHELL--OUTLINE, [Rudolf Nureyev]; COLOR PHOTO: JEFFRY D.
SCOTT--IMPACT VISUALS, [Candles in painted paper bags in honor of World AIDS Day]; COLOR·
PHOTO: CHRISTOPHER LITTLE--OUTLINE, [Elizabeth Glaser]; COLOR PHOTO: MIKE
POWELL--ALLSPORT, [Greg Louganis diving]
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�Science January 17, 1997
Copyright 1997 Information Access Company,
a Thomson Corporation Company;
ASAP
Copyright 1997 American Association for the Advancement of Science
Science
January 17, 1997
SECTION: No. 5298, Vol. 275; Pg. 298; ISSN: 0036-8075
IAC-ACC-NO: 19069852
LENGTH: 1414 words
HEAD.LINE: The media's Jove affair with AIDS research: hope vs. hype; includes related article on
Time magazine's choice of David Ho as Man of the Year
·
BYLINE: Cohen, Jon
BODY:
A casual browser of recent newsstands might conclude that AIDS is now all but cured. Last fall, the
New York Times Magazine featured a cover story headlined "When AIDS Ends." Newsweek's cover
wondered about "The End of AIDS?," and a Time cover toasted AIDS researcher David Ho as its "Man
of the Year" (see sidebar). As these magazines attest, AIDS research had a banner year in 1996,
making dramatic strides with potent new drug combinations. Indeed, Science featured the new
weapons against HIV as "Breakthrough of the Year" for 1996 (Science, 20 December, p. 1988). But
as delighted as AIDS researchers are about the progress, a growing number are concerned that many
popular media stories cross the line that s_eparates hope from hype.
Many stories do point out the drugs' shortcomings, but researchers worry that strong packaging (the
subhead to the Times Magazine story was "Notes on the Twilight of an Epidemic") often overpowers
the caveats. Lost in the fine print, for example, is the fact that the new drugs don't work on every
patient and can have serious toxicities. And if treatments don't live up to unrealistic expectations,
researchers fear a public backlash against medical science. "The hype has affected everyone -patients, physicians who know a lot about HIV, and even institutional review boards that review
clinical trials," says Roy "Trip" Gulick of New York University, who headed clinical studies that first
r.evealed the potency of the new drugs. "A Jot of people are basing their opinions and hope on
sound-bite medicine."
Even so, few researchers want to downplay the real progress that has occurred. "It's such a tightwire
one walks on," says Jay Levy, a retrovirologist at the University of California, San Francisco. "I
certainly don't want to be accused down the road that the scientific community contributed to this
hoopla .... At the same time, when you say this you sound like a naysayer."
The dramatic clinical progress -- for people who can afford the drugs -- that has grabbed the media
spotlight stems from tests of a two-pronged attack on HIV: a new class of drugs that inhibit HIV's
protease enzyme, plus existing drugs such as AZT that attack the virus's reverse transcriptase
enzyme. Studies showed that this "combo therapy" could often reduce the amount of HIV in people's
blood to below detectable levels, and the health of some sicker patients has rebounded remarkably.
But from the moment researchers first reported these data at a conference a year ago (Science, 9
February 1996, p. 755), they have raised red flags. Not only are these studies small and ongoing,
other experiments have shown that people with "undetectable" virus in their blood can harbor
masses of HIV in sites such as the lymph nodes. Also, drug-resistant strains of HIV already havE!
taken over in some patients and may eventually spoil the gains seen in most -- especially given the
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�trouble many patients have in keeping to the regimen of taking dozens of pills every day. "There's a
lot of excitement, but unfortunately I believe the situation [regarding drug resistance] is going to get
worse," says Giuseppe Pantaleo, who treats HIV-infected people at the Centre Hospitalier University
Vaudois in Lausanne, Switzerland.
One tricky distinction the media frequently oversimplifies is that the drugs tend to work best in
people who have been infected only a short time and haven't been previously treated. Researchers
say the most confusing media stories have peen about ongoing experiments aimed at clearing the
virus completely in people who start treatment within weeks Of infection. But such patients, who
have only flulike symptoms, are notoriously difficult to spot. "In the big picture of HIV infection and
disease, you're talking about a fraction of a percent of people," says Anthony Fauci, head of the
National Institute of Allergy and Infectious Diseases (NIAID). Yet, such studies have won headlines
worldwide because researchers have discussed the possibility of "curing" these individuals -- a
hypothesis that will only be tested if they stop taking their drugs.
Many leading researchers already are worried about the media cacophony that inevitably will follow if
these experiments succeed. They fear the coverage will gloss over the fact that established infections
are much harder to eradicate. "If you poll people -- even people in the field -- they're going to be
totally confused [about] whether data show eradication of virus in primary infection versus
established infections," says Fauci.
Confusing the matter even further, says Luc Perrin of University Hospital in Geneva, is that it's hard
to assess if a person is clear of HIV. Perrin's team now has five of 11 such patients with undetectable
levels of HIV in blood and lymph-node samples. But he has little faith that they have eradicated the
virus. He'd ideally like to analyze more lymphnode samples from each patient, and even then there
still might be HIV in "sanctuary" sites that can't be tested, such as the brain.
Another sobering reality is that anti-HIV drugs can have serious toxicities -- and more are certain to
surface. Just this week, the National Institutes of Health held a daylong meeting to discuss a study
done at the National Cancer Institute that showed an increase in cancer in the offspring of pregnant
mice treated with high doses of AZT. Although there's no evidence that AZT has caused cancer in
humans, the study underscores how many unknowns still exist.
Next week, the media once again will wrestle with how to spin this story when a major scientific
AIDS meeting is head in Washington, D.C. Jack Killen, head of NIAID's Division of AIDS, has some
advice. "People seem to have a need for certainty when certa.inty doesn't exist," he says. "Just
pretend you're reading a long Russian novel and you're in the middle of it."
The Reluctant Man of the Year
When David Ho learned that Time magazine was considering naming him its "Man of the Year," he
prayed that one of the other candidates for the honor would win out. "Where most people would
think of this as a cause for celebration, it's been a great source of anxiety for me," says Ho, head of
the Aaron Diamond AIDS Research Center in New York City. "I'm very concerned about the hype and
the publicity. One could bake in the spotlight [instead of] basking in it."
Ho, the first scientist to be chosen for the Time honor since a group of researchers was celebrated in
1960, didn't want to reinforce the misperception "that the AIDS epidemic was over." And he worries
mightily about the reaction of his colleagues. Although many researchers think the publicity is good
for their field, others say honoring only one person is unavoidably misleading -- which led the editors
at Time to do backflips to justify using Ho to represent all AIDS researchers in an introduction to
their package. "I'm just a poster boy for AIDS research, and in some sense for all of science," says
Ho, who played a key role recently in describing how quickly HIV copies itself.
Many of Ho's colleagues say they see him as a fine representative. "The Time 'Man of the Year' was a
wonderful thing to happen," says Robert Schooley of the University of Colorado Health Sciences
Center in Denver, who did postdoctoral work with Ho. William Paul, head of the Office of AIDS
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�Research at the National Institutes of Health, thinks the honor can only help the overall effort by
reinforcing the notion that the billions of public dollars poured into AIDS research have been well
spent.
Yet, Paul and others acknowledge that spotlighting one person for the achievement of many can be
distorting. "I think people will feel awkward about it," says Roy Gulick of New York University. In
particular, Gulick and others say the Time honorific sells short the recent discoveries of many other
Jabs, such as findings concerning HIV's abundance in lymph nodes and critical discoveries about how
HIV enters cells. Perhaps most misleading of all is the possible impression that Ho is responsible for
the success of today's drug cocktails: The new drugs were developed by industry, and the cocktails
were tested by several clinical groups, including Ho's.
Given the collective nature of these research achievements, some of Ho's colleagues have criticized
him for seeking publicity, but he says nothing could be further from the truth: "I could cure AIDS
before I could engineer a story like this."
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�- llCQUllll\;; \ uu,. • - ••"f -....- -
-
,---,
Chicago Tribune, March 1, 1998
'
Copyright 1998 Chicago Tribune Company
Chicago Tribune
March 1, 1998 Sunday, CHICAGOLAND FINAL EDITION
SECTION: PERSPECTIVE; Pg. 3; ZONE: C; ON THE RECORD.
LENGTH: 1265 words
HEADLINE: DR. DAVID HO, AIDS RESEARCHER
BYLINE: By Terry Wilson, Tribune Staff Writer.
BODY:
The scientist credited with extending the lives of thousands of people infected with HIV, Dr. David
Ho, 45, is director of New York's Aaron Diamond AIDS Research Center of the Rockefeller University.
Named Time magazine's 1996 Man of the Year, the Taiwan native engineered drugs called protease
inhibitors that when used with other medications have dramatically reduced the virus levels in
patients. Ho will be in Chicago on Thursday as keynote speaker at a community forum sponsored by
the AIDS Foundation Chicago and the federal Office of AIDS Research. On the front lines since HIV
appeared, Ho said he sees HIV becoming a disease that will most effectively be controlled in Western
countries. But, he said, "these therapies will not have a huge impact on this epidemic when you think
globally."
Q: You were 12 when you moved to the U.S. How did you adjust?
A: The most striking difference was the language. I had to start literally from the ABC's. Having been
a kid who did reasonably well in school, to not be able to communicate a single idea was traumatic.
Q: After studying at MIT, Cal Tech and Harvard Medical School to became
you encountered HIV in the early 1980s. What were you doing?
a biomedical researcher,
A: I was the chief medical resident at a hospital in Los Angeles. I still recall the initial case of a gay
man who died of what we considered very bizarre infections: parasitic infections in the lungs and the
brain and viral infections in the gastrointestinal tract. It was evident the immune system was not
functioning. We didn't know what was going on. In the first few months, we encountered five cases.
They turned out to be the initial cases of AIDS that were reported to the Centers for Disease Control.
It was clearly a new syndrome, a new disease that wiped out the immune system. We thought it
might be communicable, and that was unheard of. I developed a deep interest without realizing this
thing would turn into a worldwide plague.
Q: You also have had a chance to study the earliest samples of HIV that came from Leopoldville, a
city now known as Kinshasa in Congo. The evidence shows that a man who donated blood in 1959
had HIV. Why didn't science notice the virus then?
A: By studying the viral genes, we've dated the origin of this human epidemic to about the 1940s.
We think the related virus, simian immunodeficiency virus, jumped from monkeys in Africa (probably
from animal bites). But the number of people infected with the human version, HIV, probably wasn't
sufficient to be obvious to the few physicians who might have spotted it. The time frame raises
questions of how the virus was introduced and what caused the massive spread. It had to relate to a
lot of social factors. Central Africa was experiencing war in that period and urbanization, increases in
population density al)d, perhaps, changes in sexual behavior. All those probably contributed.
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�We estimate it has been mutating at an overall rate of about 1 percent a year, so it's a distant cousin
of the original. Within a decade or two, it would have been substantially different.
Q: When you first began testing protease inhibitors, did they do what you expected them to do?
A: We've been working with the compounds since 1990. In the lab, we knew they were very
powerful. In 1994, when we first had the opportunity to administer the first one to people, we were
pleasantly surprised that within weeks the amount of virus in the bloodstream fell not just 10-fold
but 100-fold and often 1,000-fold.
Unfortunately, in a few months, the virus developed a resistance and rebounded when the drug was
administered by itself. We saw that the virus can change very quickly when challenged, and you
really have to attack it on many fronts. From about late 1994 on, we've been using a combination of
protease inhibitors and some of the older drugs. The most remarkable results have come about from
those combination therapies.
·
Q: What did you think as you saw gravely ill people seeming to get better?
A: It's very exciting and very, very gratifying to have people who were bedridden enjoy some sort of
Lazarus syndrome. They return to a functional state and stay that way for a prolonged period.
We knew this was not going to be a happy story for all. That is why we want to be able to push the
limits to see if, in addition to controlling the virus, there might be a chance of eliminating it.
Q: We hear of mixed results, of patients who did well on so-called drug cocktails but found the
benefits later ceased. Others cannot tolerate the drugs at all. Why?
A: It's really a combination of things. There are times when the drugs are indeed toxic, and therefore
it is hard to take the regimen as prescribed. If you start to miss multiple doses every few days, that
is a formula for failure. There also are situations where patients previously have taken the drugs one
by one rather than in combination, so they don't have a chance of building a drug defense that the
virus cannot defeat. We also see a great number of people who continue to benefit.
Q: Will the drug regimen, which involves taking 15 to 20 pills per day, ever become easier?
A: Absolutely. That's something pharmaceutical companies are trying to develop: potent but simpler
regimens.
Q: Are the drugs becoming more accessible to the poor and will they become cheaper?
A: For low-income people in the U.S., there are mechanisms to get government subsidies to buy
medications. Statistics in places such as New York City and San Francisco show the drop in mortality
extends beyond whites to blacks and Hispanics. Obviously, it's not 100 percent.
I don't think the cost of the drugs is ever going to drop to a level where they're going to be
affordable to developing countries. If the cost is somewhere around $12,000 a year now, I don't
think it ever will drop to, say, $100 a year. Even that is too high for many who live in developing
countries. Unfortunately, this tremendous progress in the U.S. and Europe does not extend to areas
more severely affected.
Q: If a cure is not found, will there be a time in the next two decades when HIV will be thought of as
a chronic illness such as diabetes or high blood pressure?
·
A: In this country, we will see HIV as a more controllable disease. Unfortunately, for much of the
world, where the epidemic is spreading--in Africa and Asia--the situation is getting worse.
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�.Q: So without a vaccine, people will continue to die?
A: Unfortunately, yes. For the foreseeable future, at least, there will be no vaccine to make a dent.
Q: What do you think about physicians who want to inject themselves with an altered form of the
virus?
A: They would use the very vaccine that has been demonstrated to be protective in monkeys. It's a
live-virus vaccine, though weakened. How safe is that? It has been shown that such a vaccine could·
kill newborn monkeys and could probably kill 1 in 20 adult monkeys. If we're talking about a vaccine
that is going to be administered on a large scale to a lot of uninfected people, that safety profile is
not good enough.
While these physicians deserve applause for their bravery, I just don't think any of the officials will
allow it to proceed.
Q: Can you put HIV into perspective in terms of other plagues that humanity has survived?
A: It has a very short history, yet has become one of the world's major killers. It has achieved the
same rank as malaria and tuberculosis and is rapidly getting worse. In another 10 years, it could
become the major killer. It's quite important.
An edited transcript
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�David D. Ho
..... One of the leading pioneers in AIDS research
X- fll f
Birthdate
Nov. 3, 1952 in Taiwan
Occupation
Medical researcher
Parents
Paul and Sonia Ho
David Da-1 Ho is leading the world
to fight AIDS. He has been
identified as a leading pioneer in this
field of AIDS research and was
. selected as 1996 man of the year by
Time Magazine for his
contributions. His quantitative
techniques for measuring viral
burden have been widely adopted by
clinical investigator world-wide.
Family
Married Susan
Two daughters and a son
Education
• BS, physics, California
Institute of
Technology, 19711974
• PhD, Harvard Medical
School, 1974-1980
Before AIDS got its name, Ho was
already treating AIDS patients and
doing research on this disease. He
began to focus on AIDS research
when he was in Massachusetts
General Hospital. Four years later,
he moved back to Los Angeles and
taking a faculty position in the
School of Medicine in UCLA and
continued his research on AIDS.
Career
• Teaching at the School
of Medicine in
University of California
at Los Angeles, 19871990
• Director, Aaron
Diamond AIDS
Research Center, New
York, 1990·
Awards
• TIME Magazine's Man
of the Year, 1996
Ho immigrated with his family to
Los Angeles at the age of 12 and
finished his high school and college
education in the Los Angeles area
before attending Harvard medical
school. Although Ho loves physics
and majored in physics in his
undergraduate study, he decide to
choose Medicine as his life career.
He explained why he made such a
decision to Time Magazine, " the
most glittering prizes in science
weren't in physics. Molecular
biology was the cutting edge.
Medical research was much more
tangible".
Recently, Ho's novel use of a
"cocktail" of protease inhibitors and
other antiviral drugs in the earliest
http://www .chineseinc.com/36002.htm
1/3/2001
�stages of infection has shown
remarkable promise in beating back
the AIDS virus and lit up the hope
of AIDS patients.
• The Man ofthe Year: Dr.
David Ho. Time Magazine,
Dec. 30, 1996.
• Dr. David Ho. A Magazine,
volume 2, no. 3, 1994. Page30
Home I Introduction I Business profile I Who's who I Business SIC I Business groups I FAO & Help
1999 Chinese Registry
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�THEBODY:AN
Alt>S AND HtV
INfORMATfON
RESOURCE
How Far Can You Knock Down
HIV?
An Interview with David D. Ho, MD
by Mark Mascolini
•
•
•
•
•
•
•
Introduction
The primary infection experiment
Not just "math and modeling"
Thinking ahead with anti-HIV regimens
"Not a time to pull back" on quest for new drugs
The eradication wager
References
When attempting to write a pithy preamble to an interview with David
Ho, one is tempted to consult the latest edition of The Toastmaster's
Handbook for snappy_ alternatives to the much-abused "Our speaker
tonight needs no introduction." Even before the December 30, 1996
issue of Time, telling this Journal's readers something new about the
director of the Aaron Diamond AIDS Research Center would have
been difficult.
But perhaps there is a way to illumine further his contribution to HIV
research, and that is to announce here that the Journal has selected Ho
as the first recipient of what is certain to become a highly coveted
prize: Author of the Most-Stolen Slide of the Year award. In fact, if the
Journal had begun bestowing this trophy a few years back, Ho would
now have at least three platinum AMOSSYs festooning his office. The
first would commemorate the celebrated image from his 1989 New
England Journal article(l) demonstrating astoundingly high titers of
HIV in plasma and PBMCs of seropositive people with and without
AIDS-defining symptoms. The second would show plummeting levels
of plasma RNA in people whose steady state of viral replication had
just been perturbed by a protease inhibitor,(2) evidence that led to the
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�current view of viral dynamics. The third would outline the
"compartments" in which HIV is sequestered,Q_) and from which Ho
and others hope it can be pried by a few years of aggressive
antiretroviral therapy.
The cloning of these figures by countless speakers has elevated them to
near-iconographic status. More importantly, they trace the
uninterrupted stream of clinical research through which Ho arid his
colleagues have helped transform the treatment of HIV infection, and
they testify to the frequent superiority of visual to verbal suasion when
trying to change minds. But the Journal allowed Ho to rely solely on
words when interviewing him at the April Keystone Conference on
AIDS Pathogenesis. (A report on this conference will appear in the July
issue of the Journal.)
The primary infection experiment
Journal: Have there been any breakthroughs in viremia
in your study of treatment for primary HIV infection?
Ho: We have 20 patients who remain on the study, taking
either indinavir or ritonavir with AZT plus 3TC. Everyone
is still aviremic. Most of them have now had tissue
biopsies, tissue cultures, tissue in situ hybridization and
PCR, and these assays have shown no evidence of ongoing
HIV replication. The patient treated for the longest time
has been on therapy for about 21 months. Because these
patients began treatment so early, their immune responses
are good. Their CD4 counts are high, if not completely
normal, and the CD4/CD8 ratios are generally above 1. So
everyone is doing well and we're very pleased with the
results. We're getting to the point where some of the
patients who have been treated longer are coming around
to have a second set of biopsies. We've been taking gut
biopsies that contain lymph follicles ·and are planning to
biopsy lymph nodes and -- if patients have them -- tonsils.
We're also going to do spinal taps for cerebrospinal fluid.
All of these samples will be assessed to make sure there's
really no evidence of active virus replication. And, at that
juncture, we would think about stopping medication in
some of these individuals.
Journal: When you get to that point, let's assume that
some people agree to stop...
Ho: We already know that several patients would like to
stop to see what would happen.
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�Journal: You've said you want to continue treatment for
two and a half to three years before you stop. When you
do stop, how long would it take for you to be convinced
that the therapy had worked and had eradicated the
virus?
Ho: We're in uncharted territory here. We really don't
know, but we have the feeling from previous observations,
when therapy was stopped earlier, that when HIV returns it
returns quickly. We plan to monitor the patients very, very
frequently and carefully, and I think we will feel pretty
good if we don't see any virus in the first month or two.
Obviously, there could be a late appearance, but knowing
how quickly HIV doubles, we really should see detectable
levels of virus within days or weeks -- unless there's
something we don't understand. In that case there could be
occurrences months or years later. Obviously, we will
continue to follow these patients very carefully even if
HIV can't b'e detected in the first few months after
treatment stops.
Journal: Let's say that it doesn't work and virus isn't
eradicated in these studies. Based on what's known now,
are there still good reasons to start treating people with
primary infection, even if you can't clear the virus?
Ho: The only patient data to justify intervention during
primary infection is the study by Perrin and his colleagues
in Geneva.(1) They showed that, over the short term, AZT
treatment of primary infection has some clinical benefit
compared with placebo. Beyond that, I don't think there's
any real information to guide us. I think we have to rely on
our current understanding of what HIV does and what the
drugs do in other settings: since there's now growing
evidence that multidrug combination therapy is better than
monotherapy or dual therapy ,(5-7) and since we know we
get the best viral response when the patient is treated
earlier, one could extend that logic to the _primary setting.
But that's only a theoretical argument rather than
something that's supported by clinical data at this point.
Journal: You've been careful to say that you think of
these studies as proof-of-concept studies rather than as
an attempt to establish a standard of care. But what
exactly does that mean? There are some clinicians who
already have adopted this strategy as the standard of care
for primary HIV infection. Do you think they shouldn't
until your results and those of others are more mature?
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�ri1~C
"t Ul l.J
Ho: It would be incorrect for me to say that clinicians
should or should not do certain things if they see a patient
with primary infection, simply because there's not much
data. So I am not going to come out and propose a certain
therapy and speak against other approaches. I know what I
would do clinically, but you have to remember that what
we're doing in these patients is an experiment. Our initial
question was not whether HIV could be eradicated, it was
how far down we could knock HIV with the most potent
therapy at the time. Then, when the first results looked
promising, the question got extended to whether HIV can
be eradicated.
But what we're doing is an experiment, and when you're
doing an experiment to prove a principle, you want to set it
up in a more or less idealized manner. So you begin by
saying, "Obviously it's easier to treat earlier than later."
Then logically you move "early" to "as early a possible,"
when the viral population is as homogeneous as possible
and there are the fewest viral variants to deal with. As a
result the chance of success goes up by some factor -- we
don't know how much.
That's how this experiment came. about, but people
sometimes forget that and think we should be doing other
things. They have different questions, but they want us to
answer them. For example, some people think that we
ought to have a control group. But that's not the question
we asked. Our experiment is not designed to show
improved prognosis with an early treatment group
compared with an untreated group. Our question was how
far down we could knock this virus as early as possible. So
if some people want to ask different questions, they should
ask those questions in different trials.
But some clinicians, as you point out, have begun to treat
people with primary infection, simply because the early
results of our study and others are so dramatic. And it may
tum out to be the correct strategy, but I think time will
have to tell.
Return to Contents
Not just "math and modeling"
Journal: What are the most troubling misconceptions
about your work on viral dynamics?
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�-----------
·--
•
••------~-----,
.A.Y---
Ho: I think the viral dynamics modelQ) is accepted by
most workers in this field. Everyone may not understand
the full details of the different viral turnover rates in each
of the compartments-- productively infected CD4
lymphocytes, latently infected T cells, macrophages, and
so on -- but I think those details are gradually becoming
better understood. If people don't understand the details,
they do know that there's very rapid turnover and that HIV
infection is characterized by this persistently active
process.
But there are technical details on which there are general
misconceptions. People think we study only viral particles,
but by studying viral particles we're really studying the
cells that make them. That's obviously more important.
Another common misconception is that all of our work on
viral dynamics is just theory. They say, "Oh, that's math
and modeling." Those who think that way generally have
not read the work carefully or listened to the presentations
carefully. They think we're just pulling things out of the
air. In reality what we do is go and gather patient
information, and we try to be very quantitative and precise
with the analysis of patient data. It's this analysis that relies
on mathematical approaches-- but it's analysis of hard
clinical data.
Journal: You mentioned in your presentation the other
night that you don't disagree with the finding of Frank
Miedema's group that telomeres~ on the chromosomes of
CD4 cells in people w_ith HIV infection are not unusually
shortened,(8) but you think their interpretation of that
finding is wrong. Their interpretation is that CD4 T
lymphocytes are not turning over as rapidly as you and
your colleagues calculate. How do you square their
results with your calculations of CD4 -cell turnover?
Ho: I think the whole field would have to be turned upside
down if they turned out to be right. There's just too much
staring them in the face. You take the data that CD4
telomeres are not shortened, and you say, "Let's see what
the explanations are." One of them is that CD4 cells are
not turning over rapidly, and that's the interpretation they
adopted. But there are two other explanations as well. One
is that telomerase activity is enhanced in people with HIV
infection, and that that's what keeps the telomeres close to
their normal length. Miedema's group argues that they
have done assays to measure telomerase activity and didn't
find that it is enhanced. But I would argue that their assays
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�are not sensitive enough to measure telomerase activity in
cells from these patients. You want to be very sensitive
and very accurate when the range of activity is very small,
because a difference of 0.1 percent and 0.5 percent can be
substantial. But the assay system they used can't determine
such small differences reliably. You have to use modified
assays, which are available in the field. So the issue of
telomerase activity is unresolved.
A more important issue is that when you assay the
telomere length of a mixed cell population, you have to
know something about population dynamics. If I give you
an extreme example, this becomes very evident. Let's say
we have 100 cells, and 50 are turning over rapidly. If these
50 that are turning over rapidly are preferentially
eliminated by HIV, which infects activated cells, they're
gone and you're left with the 50 that are not turning over.
You measure the telomere lengths of these 50 remaining
cells and they're normal. So, because the cells that are
turning over are gone, you conclude that there's no
turnover. Nothing could be further from the truth. This is
why we haven't published our results, because we don't
think you can analyze it in such a simplistic manner.
In fact, people who have done modeling and careful
thinking about cell dynamics immediately realize that the
cell you're looking for is the cell that's disappearing from
the sample. Modelers like Alan Perelson [who works with
the Aaron Diamond group] and Rob de Boer [who works
with Miedema's group and other Dutch investigators] have
gone through these results and have shown that the data
are consistent with a high turnover and a preferential
elimination of the cells that are turning over. HIV goes for
activated cells that are turning over. That aside, if you just
think about how many cells are expressing the activation
antigen -- the cell cycling antigen -- it's pretty clear that
their conclusion cannot be right. Plus, I think the
experiments we are doing now, labeling T cells in
monkeys exposed to virus, will show that their conclusion
is not right.
Journal: Another question raised about your work is the
significance ofproviral HIV DNA. You say that the
proviral DNA that can be detected in latently infected T
cells months after fully suppressive therapy begins
represents "archival dead sequences." But Bob Siliciano
at Johns Hopkins reported at this meeting and elsewhere
(l!l) that the tiny amount of integrated HIV DNA he
finds in resting cells is replication competent.
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�1
Ut;""'
I
VI :L;:J
Ho: There's no inconsistency between his findings and our
analysis of viral turnover. In our analysis we also looked
for a pool of latently infected cells with an infectious
genome, and we know we have a pretty good idea of its
turnover rate. Bob is looking at untreated individuals, and
that small population of latently infected calls-- the ones
with integrated DNA capable of making replicationcompetent virus -- is turning over. Our studies indicate
that, after six months or so of therapy, all of those latently
infected cells should be gone because their average halflife is about a week. So the remaining viral DNA that can
be detected after months of therapy is not the replicationcompetent fortn he's speaking of. It would be the other
[turning over] form that he's talking about.
Whether integrated or not, they're defective. We know that
because, let's say nine months into therapy, the patient still
has 1000 copies of proviral DNA per million cells. That's a
fair amount of viral DNA. Yet, no matter what you do with
those cells, you cannot activate them into releasing mv.
Obviously you could come up with fancy explanations of
why these cells containing viral DNA cannot be activated
to produce new virions, but the straightforward
explanation is that the DNA is defective. And that
explanation is consistent with a large literature showing
that most viral DNA is defective .
. Return to Contents
Thinking ahead with anti-HIV regimens
Journal: I want to ask you just a couple of questions
about the majority of people with HIV infection -- those
who test positive years after being infected. Right now
they have a diffwult choice to make because lots of
factors argue for starting maximally suppressive therapy.
On the other hand, given the drugs available right now,
drug-naive people with chronic infection have to be
concerned that if they start AZT, 3TC, and indinavir, for
example, and if that combination fails, they've probably
blown their chance to get maximal benefit from another
protease inhibitor combination. What can you say to
those patients when they're trying to make those
decisions?
Ho: I would say, "Let's find out where you are in the
course of IDV infection." I think if viremia levels are high,
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�let's arbitrarily pick a number of 5000 HIV RNA copies or
higher -- then it's best to go ahead and treat. Of course,
every physician has a different comfort level when it
comes to an RNA threshold, but I think most physicians
would recommend starting treatment now if they think the
viral load is too high. But if the viral load is lowish, then I
think there's a more difficult decision to be made between
observing carefully and not treating, or going ahead and
starting therapy.
When you do start therapy, obviously you should not just
think about immediate therapy, with the combination you
mentioned, for example. Clinicians should think about one
regimen and a second regimen. Construct a regimen that is
good and potent, then think, "If that should fail, what
would be the next option?" Fortunately, given the drugs
that are available-- two NNRTis, five nucleoside RT
inhibitors, four licensed protease inhibitors, with more of
each in the pipeline-- I think one could come up with two,
possibly three comb.inations that are reasonable to go with.
And I generally recommend thinking ahead that way -- if
the patient is drug naive. Unfortunately, the problem is that
so many patients are drug experienced.
Journal: A difficult moral issue has arisen about starting
antiretroviral therapy. Some clinical investigators are
saying, "I won't start a combination including a protease
inhibitor in a patient I don't think will be compliant,
because resistance.will emerge and that's bad for the
patient and bad for public health. " At the same time
some clinical investigators are saying, "Ifyou don't start
with maximal therapy, don't start at all, because the.
virus will become resistant more quickly to suboptimal
therapy." Both arguments seem to make sense. Is there
any way out of that dilemma?
Ho: I appreciate the problem. I'm not sure I have any real
answers to that tough question. You're getting into an area
where the discussion needs involvement by ethicists and
people who are doing behavioral studies. I think this is
beyond my level of expertise. I face the same problems and
participate in these discussions, but I think this is an area
that requires input from experts other than clinical
investigators.
Return to Contents
"Not a time to pull back" on quest for new
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�drugs
Journal: You were the person who showed that the first
attempt to block the primary receptor of HIV -- with
soluble CD4 -- was destined to fail.(W Do you think
there's any better chance offinding agents that will
effectively block secondary receptors?**
Ho: I think they will find small agents that will block
secondary receptors, but I think this overall strategy is a lot
tougher than many people appreciate. Many of the experts
here at this conference know that once you find a small
chemical blocker, you still might not have an effective
therapy because there are so many alternative pathways by
which the virus can enter the cell. So I think this strategy
won't be easy. If blocking the principal receptor did not
work so well, why would blocking a secondary receptor
work any better, especially when there are multiple
secondary receptors? And if you block CCR5, for
example, those IllV variants that favor, say, CXCR4,
might well have a selective advantage. In that case, are you
doing the patient a favor by blocking CCR5? There's a real
debate, but clearly we won't know for sure until such an
experiment is done. Perhaps one could do some of these
experiments in monkeys. So I view that as a very, very
tough problem. I have no doubt that the pharmaceutical
companies, once they set up their screens for inhibitors of
CCR5 and gp120 interaction, will find "hits" and that
"hits" will be developed. But ultimately how effective they
will be in patients, I don't know.
Journal: Do you think it's going to be necessary to
develop other classes of drugs besides nucleosides,
NNRTis, and protease inhibitors? Let's say that drug
developers succeed in making really tolerable protease
inhibitors.that are even stronger than the ones licensed
now, and that they can be combined with a new
generation·of better nucleosides and good
nonnucleosides. Are clinicians really going to need
integrase inhibitors and chemokine receptor blockers?
Ho: Without getting into social, political, and economic
issues, overall my answer would be that-- although we've
made tremendous therapeutic advances against mv -- we
haven't gotten to the point of curing patients. So this is not
a time to pull back on the development of new drugs. I
think if we're beating up on the virus a little bit, now is the
time to really go after it and come up with a few more
agents, hoping that these few more, when added on top of
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�what we have, could do the trick. That's how I view it.
The other thing, as you know, is that these meds are not
without side effects. We need newer agents. Hopefully, we
can come up with equally potent or more potent agents
with fewer side effects. That's how the antibiotic field
evolved. Who knows? Maybe some integrase inhibitor, for
example, could be a small chemical that's very easy to
make, and one could make buckets of that stuff for very
little compared with the protease inhibitors. And if those
agents are as active or more active, then you could see
some of the newer agents replacing the old ones, with
tremendous benefit to the patient and to society if the cost
factor is a substantial one.
So I think there are multiple reasons to push ahead. There
are people from the pharmaceutical industry who say,
"Well, we've come so far with the new protease inhibitors
and the RT inhibitors doing such a great job, we should
just back off." My reply is the one I've just given you.
That's quite the wrong attitude.
Return to Contents
The eradication wager
Journal: Your colleague John Moore has argued
strongly that certain basic questions about HIV vaccines
have to be answered before investigators can proceed to
large-scale efficacy trials. What do you see those
questions as, and how close do you think vaccine
research is to answering them?
Ho: Let me just clarify John's point a little bit. You
summarized it well by saying he believes we should not
proceed with large efficacy trials at this point. I would
agree with that. But that doesn't preclude clinical research
going on right now. I think we need to have basic research,
and we need to have clinical testing of new strategies to
get information in patients. We can'tjust do everything in
the laboratory and figure things out that way. So it will
have to be an integrated process between the clinic and the
laboratory, back and forth.
But I agree that we are not ready for large-scale trials
involving thousands of patients. I really do think we need
to understand more about what protects against HIV
infection. These mysterious correlates of protection are
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�still not well understood. We have a vaccine that works in
monkeys, the live attenuated SIV [simian immunodefiency
virus] vaccine, but we don't know how it protects. Is it a
CTL [cytotoxic T lymphocyte] response? Is it an antibody
response? Is it something else? We need to understand that
because that will guide us. I think most people will agree
that, while the live attenuated virus strategy is very
efficacious in the monkey model, it's not a strategy that
will be adopted for humans any time soon -- anywhere.
But we can use that system to understand what's going on,
and hopefully once we understand what the mediators of
protection are, then we can think of other safer strategies to
induce them.
Of course there are many other questions. Once you've
decided on an approach you also have to decide how to
present that antigen to the immune system to elicit the
effect you're looking for. So there are many issues, and
many of these things are not well worked out.
Journal: My last question has to do with how far HIV
research has come and how far you think it has to go.
Let me put it to you this way: There are about a million
people in the United States who have HIV infection. How
many of them do y'ou think wiU die of AIDS?
Ho: Without giving you specific numbers, I think there's a
good chance that this population of one million infected
people will get substantial benefit from the current
therapies, so that their life span could be lengthened
substantially by the developments of the past few years and
by the developments that will be coming in the next five
years.lf the eradication of HIV is possible, I think there's a
chance that, some time down the line, a portion of the
people infected today could come to benefit from this
development. You have to put your money down
somewhere on the situation. And I think that's a reasonable
wager to make.
Return to Contents
Mark Mascolini writes about HIV (mailmark@postoffice.ptd.net).
=Telomeres, repeated sequences on the tips of chromosomes, become
shortened as cells divide. As a result, the telomere length of a cell
population can be used as one measure of how "aged" that population
is -- in other words, how often it has "turned over." For example, both
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1/3/2001
�••• - - - - - - · · _ _ _ ...... _ ,
.£. • ..........,.
Page I
Miedema's group and researchers at the University of California, Los
Angeles,(2_) determined that the telomeres of CDS T lymphocytes in
people with HIV infection are about as short as those of healthy 100year-olds and concluded that this is proof of the constant activation of
CDS cells by HIV. Miedema's interpretation of his CD4 telomere data
is more controversial.
**For a review of recent developments in this field, see reference (12).
References
L Ho DD, Moudgil T, Alam M. Quantitation of human
immunodeficiency virus type 1 in the blood of infected persons. N Engl
J Med 1989;321:1621-1625.
2. Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover ofplasma
virions and CD4lymphocytes in HN-1 infection. Nature
1995;373:123-126.
3. Perelson AS, Neumann AU, Markowitz M, et al. H1V-1 dynamics in
vivo: virion clearance rate, infected cell lifespan, and viral generation
time. Science 1996;271:1582-1586.
~'Kinloch-de LoesS, Hirschel B, Hoen B, et al. Zidovudine versus
placebo in primary HN infection: a randomized study. N Engl J Med.
1995;333:408-413.
. 5. Gulick RM, Mellors J, Havlir D, et al. Potent and sustained
antiretroviral activity ofindinavir (IDV), zidovudine (ZDV) and
lamivudine (3TC). Presented at the XI International Conference on
AIDS; July 7-12, 1996; Vancouver. Abstract Th.B.931.
6. Hirsch M, for the Protocol 039 (Indinavir) Study Group. Indinavir
(IDV) in combination with zidovudine (ZDV) and lamivudine (3TC) in
ZDV-experienced patients with CD4 counts <50 cells/mm3. Presented
at the 4th Conference on Retroviruses and Opportunistic Infections;
January 22-26, 1997; Washington, DC. Abstract LB7.
7. Conway B, Montaner JSG, Cooper D, et al. Randomized, doubleblind one-year study of the immunologic and virologic effects of
nevirapine, didanosine and zidovudine combinations among
antiretroviral naive, AIDS-free patients with CD4 200-600. Presented
at the Third International Congress on Drug Therapy in HIV Infection;
November 3-7, 1996; Birmingham, UK. Abstract OP7.1.
~Walthers
KC, Wisman GBA, Otto SA, et al. Tcell telomere length in
HIV-1 infection: no evidence for increased CD4+ cell turnover.
Science 1996;274:1543-1547.
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�
Dublin Core
The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.
Title
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Heather Hurlburt
Creator
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Office of Speechwriting
Heather Hurlburt
Date
A point or period of time associated with an event in the lifecycle of the resource
1999-2001
Is Part Of
A related resource in which the described resource is physically or logically included.
<a href="http://clinton.presidentiallibraries.us/items/show/36161" target="_blank">Collection Finding Aid</a>
<a href="https://catalog.archives.gov/id/7431953" target="_blank">National Archives Catalog Description</a>
Identifier
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2008-0700-F
Description
An account of the resource
Heather Hurlburt's speechwriting collection consists of speeches, drafts, correspondence, and background research. Hurlburt worked as Special Assistant and Speechwriter to President Clinton. Her speechwriting files date from 1999-2001. As a speechwriter, Hurlburt prepared remarks on primarily domestic issues ranging from health care to the Special Olympics to the Mississippi Delta Region to the Kennedy Center Awards. She wrote remarks for policy speeches, radio addresses, commencements, taped video remarks, and award ceremonies or tributes. She also prepared a few speeches for the First Lady, and one undelivered speech for Sandy Berger on the topic of military reform.
Provenance
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Clinton Presidential Records: White House Staff and Office Files
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William J. Clinton Presidential Library & Museum
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128 files in 11 boxes
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Paper
Dublin Core
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Title
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Citizen's Medal 1/8/01 [Remarks] [Daniel Ho]
Creator
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Office of Speechwriting
Heather Hurlburt
Identifier
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2008-0700-F
Is Part Of
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Box 11
<a href="http://www.clintonlibrary.gov/assets/Documents/Finding-Aids/2008/2008-0700-F.pdf" target="_blank">Collection Finding Aid</a>
<a href="https://catalog.archives.gov/id/7431953" target="_blank">National Archives Catalog Description</a>
Provenance
A statement of any changes in ownership and custody of the resource since its creation that are significant for its authenticity, integrity, and interpretation. The statement may include a description of any changes successive custodians made to the resource.
Clinton Presidential Records: White House Staff and Office Files
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William J. Clinton Presidential Library & Museum
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Adobe Acrobat Document
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Reproduction-Reference
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12/15/2014
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42-t-7431953-20080700F-011-002-2014
7431953