From: THE NEW YORKER - 22.12.2014
BY: Dr. Jerome Groopman
Current research is
targeting the ability of H.I.V. to stay dormant in c cells memory cells.
One morning in the winter of 1981, my wife came
home after her on-call shift at the U.C.L.A. Medical Center and told me about a
baffling new case. Queenie was an eighteen-year-old prostitute, his hair dyed
the color of brass. He had arrived at the emergency room with a high fever and
a cough, and appeared to have a routine kind of pneumonia, readily treated with
antibiotics. But the medical team retrieved a microbe from his lungs called Pneumocystis
carinii. The microbe was known for causing a rare fungal pneumonia that had
been seen in severely malnourished children and in adults undergoing organ
transplants or chemotherapy.
Several specialists at the hospital were enlisted to make sense of the
infection. Queenie had a critically low platelet count, which made him
susceptible to hemorrhage, and I was called in to examine him. He was lying on
his side and breathing with difficulty. His sheets were soaked with sweat. A
herpes infection had so severely blistered his flesh that surgeons had cut away
necrotic segments of his thighs. I couldn’t explain his falling platelet
numbers. His lungs began to fail, and he was placed on a ventilator. Soon
afterward, Queenie died, of respiratory failure.
His was one of several cases of the same rare
pneumonia seen by physicians on both coasts. Michael Gottlieb, a U.C.L.A.
immunologist, studied the blood of some of these patients and made the key
observation that they had lost almost all their helper T cells, which protect
against infections and cancers. In June, 1981, the Centers for Disease Control
published Gottlieb’s cases in itsMorbidity and
Mortality Weekly Report, and, in July, Dr. Alvin Friedman-Kien, of New York University,
reported that twenty-six gay men in New York and California had received
diagnoses of Kaposi sarcoma, a cancer of the lymphatic channels and blood
vessels. This, too, was strange: Kaposi sarcoma typically affected elderly men
of Eastern European Jewish and Mediterranean ancestry.
I tended to our Kaposi-sarcoma patients. I was the
most junior person on staff and had no expertise in the tumor, but none of the
senior faculty wanted the job. My first patient, a middle-aged fireman
nicknamed Bud, lived a closeted life in West Los Angeles. Not long before he
checked in to the hospital, he had started to find growths on his legs that
looked like ripe cherries. Then they appeared on his torso, on his face, and in
his mouth. Despite strong doses of chemotherapy, the standard treatment for
advanced Kaposi sarcoma, his tumors grew, disfiguring him and killing him in
less than a year. By 1982, men with highly aggressive kinds of lymphoma had
started to arrive at the hospital. They, too, failed to improve with
chemotherapy. Patients were dying from an array of diseases that had overcome
ravaged immune systems. All my patients had one disorder in common, which the
C.D.C., that year, had named acquired-immunodeficiency syndrome, or AIDS. Scientists did not yet know what caused it.
The next year, two research teams—one led by Luc
Montagnier and Françoise Barré-Sinoussi, of the Pasteur Institute, in Paris,
the other by Robert Gallo, at the National Cancer Institute, in
Maryland—published papers in Science that described a new retrovirus
in the lymph nodes and blood cells of AIDS patients. A retrovirus has a
pernicious way of reproducing: it permanently inserts a DNA copy of its genome
into the nucleus of a host cell, hijacking the cell’s machinery for its own
purposes. When the retrovirus mutates, which it often does, its spawn becomes
difficult for the body or a vaccine to target and chase out. Retroviral
diseases were widely believed to be incurable. In May of 1986, after much
dispute about credit for the discovery (the French finally won the Nobel, in
2008), an international committee of scientists agreed on the name H.I.V., or
human immunodeficiency virus. By the end of that year, about twenty-five
thousand of the nearly twenty-nine thousand Americans with reported AIDS diagnoses had died.
Since then, H.I.V. has been transformed into a treatable condition, one
of the great victories of modern medicine. In 1987, the F.D.A. approved AZT, a
cancer drug that had never gone to market, for use in H.I.V. patients. At
first, it was extortionately priced and was prescribed in high doses, which
proved toxic, provoking protest from the gay community. But AZT was able to
insinuate itself into the virus’s DNA as it formed, and later it was used in
lower doses. Scientists have now developed more than thirty antiretroviral
medicines that stop H.I.V. from reproducing in helper T cells.
The idea of combining medications into a “cocktail”
came in the mid-nineteen-nineties, mirroring the way oncologists treated
cancer. Cancer cells, like H.I.V. particles, can mutate quickly enough to
escape a single targeted drug. The treatment regimen—HAART, for highly active antiretroviral therapy—was put
through clinical trials by prominent researchers such as David Ho, of the Aaron
Diamond Institute, in New York. I gave the cocktail to one of my patients,
David Sanford, and less than a month after beginning treatment his fever fell,
his infections disappeared, his energy returned, and he started to gain weight.
The H.I.V. in his bloodstream plummeted to an undetectable level, where it has
remained. Later, in a Pulitzer Prize-winning article, Sanford wrote, “I am
probably more likely to be hit by a truck than to die of AIDS.” That now holds true for a great majority of
people with H.I.V. in the United States. In the past five years, not one of the
dozens of H.I.V. patients I’ve cared for has died of the disease.
There are still tremendous hurdles.
Thirty-five million people in the world are living with the virus. In
sub-Saharan Africa, where most new cases are reported, sixty-three per cent of
those eligible for the drug regimen do not receive it; those who do often fail
to receive it in full. In the United States, a year’s worth of HAART costs many thousands of dollars per patient,
and the long-term side effects can be debilitating.
Now researchers are talking more and more about a cure. We know as much
about H.I.V. as we do about certain cancers: its genes have been sequenced, its
method of infiltrating host cells deciphered, its proteins mapped in three
dimensions. A critical discovery was made in 1997: the virus can lie dormant in
long-lived cells, untouched by the current drugs. If we can safely and
affordably eliminate the viral reservoir, we will finally have defeated H.I.V.
Ward 86, the nation’s first outpatient AIDS clinic, opened at San Francisco General
Hospital on January 1, 1983. Recently, I went there to see Steven Deeks, an
expert on the chronic immune activation and inflammation brought on by H.I.V.
Deeks, a professor at the School of Medicine at U.C.S.F., also runs the SCOPE Study: a cohort of two thousand
H.I.V.-positive men and women in whom he measures the long-term effects of
living with the virus. Each year, blood samples are sent to labs all over the
world. Deeks’s mission is to catalogue the damage that H.I.V. does to tissues
and to test new drugs that might help.
The ward occupies the sixth floor of an Art Deco
building on the north side of campus. I found Deeks in his office, wearing a
flannel shirt and New Balance sneakers. He explained his concerns about the
drug cocktail. “Antiretroviral drugs are designed to block H.I.V. replication,
and they do that quite well,” he said. But they don’t enable many patients to
recover fully. The immune system improves enough to prevent AIDS, but, because the virus persists, the immune
system must mount a continuous low-level response. That creates chronic
inflammation, which injures tissues.
The inflammation is exacerbated by side effects of
the medicines. Early treatments caused anemia, nerve damage, and
lipodystrophy—the wasting of the limbs and face, and the deposits of fat around
the belly. Lipodystrophy is still a major problem. Deeks has observed many
patients in the SCOPE cohort with high levels of
cholesterol and triglyceride, and these can lead to organ damage. One serious
consequence is heart disease, which appears to be caused by inflammation of the
artery walls. Deeks has also seen lung, liver, and skin cancers in his
patients. In a disturbing echo of the early days of the epidemic, he has
noticed that middle-aged patients develop diseases associated with aging:
kidney and bone disease and possibly neurocognitive defects. A better definition
for AIDS, according to Deeks, might be
“acquired-inflammatory-disease syndrome.”
He introduced me to one of his patients, whom I’ll call Gordon. A tall,
genial man with rimless glasses stood up to shake my hand, and I saw that he
had the signature protruding belly. He has been H.I.V.-positive for almost
forty years, and he said he felt lucky to be alive: “A ten-year partner of mine
who had the same strain of H.I.V., who ate the same food, had the same doctors,
took the same early H.I.V. meds, died in June, 1990, almost twenty-five years
ago.”
He told me, “I’m no longer that concerned about the virus itself. I’m
more concerned about my internal organs and premature aging.” In 1999, at
fifty, he learned that fatty deposits had substantially constricted the blood
flow in a major artery that supplies the heart’s left ventricle. He began to
experience crippling pain when he walked, because the blood supply to his bone
tissue had diminished—a condition called avascular necrosis. In 2002, he had
his first hip replacement, and the second in 2010. His muscles have shrunk, and
sitting can be uncomfortable, so he sometimes wears special foam-padded
underwear. Every other year, he has his face injected with poly-L-lactic acid,
which replaces lost connective tissue.
Gordon’s longevity, and the dozens of drugs he has
taken to stay alive, exemplifies the experience of millions of infected AIDS patients. His state-of-the-art treatment
costs almost a hundred thousand dollars a year. Although it’s covered by his
insurance and by the State of California, he calls it “a ransom: your money or
your life.” For Deeks, the question is “Can the world find the resources to
build a system to deliver, on a daily basis, antiretroviral drugs to some
thirty-five million people, many in very poor regions?” He is doubtful, which
is why he is focussed on helping to find a cure. “Our philosophy is that in
order to cure H.I.V., we need to know where and why it persists,” he said.
In 1997, amid euphoria about HAART, people first started thinking seriously about a
cure. Sooner or later, all infected cells die on their own. Could the right
drugs in the right combination rout the virus for good? That year, David Ho
published a paper in Nature in which he mathematically
predicted that an H.I.V. patient on the HAART regimen should be able to conquer
the detectable virus in twenty-eight to thirty-seven months. That issue also contained
a very different report from Robert Siliciano, currently a Howard Hughes
investigator at the Johns Hopkins School of Medicine. Using an uncommonly
sensitive measurement technique that he’d invented, Siliciano located H.I.V. in
a type of helper T cell that provides memory to our immune system and normally
survives for decades. Memory T cells are uniquely important: they recognize the
antigens in infections and orchestrate speedy responses. But the virus proved
to be even cleverer. It lay dormant in strands of host DNA, untouched by the
drug cocktail, later springing back to life and degrading the immune system.
At sixty-two, lanky and circumspect,
Siliciano is highly regarded in the tight-knit community of H.I.V. researchers.
He met his wife and collaborator, Janet, in the nineteen-seventies, when she
was a graduate student at Johns Hopkins, studying the proteins that T cells
release when they encounter microbes. Now fifty-nine years old, with curly red
hair and a hint of a New Jersey accent, Janet joined Bob’s lab after his paper
appeared in Nature. She said that the idea was his,
but Bob told me that Janet developed it over the next seven years, tracking the
levels of dormant virus in patients consistently treated with HAART. Her data confirmed his thesis: the virus could
survive almost indefinitely. “We calculated that it would take seventy years of
continuous HAART for all the memory T cells to
die,” she said.
Siliciano told me about the first time he saw the
latent virus emerge in the memory T cells of an H.I.V. patient on HAART. The patient was thought to be cured. “He had been
biopsied in every imaginable place, and nobody could find any virus,” Siliciano
said. Researchers took twenty tubes of the patient’s blood, isolated the T
cells, and divided them into multiple wells. The specimen was then intermixed
with cells from uninfected people. If the healthy T cells became infected, the
virus would reproduce and be released. Detection of the virus would be
signalled by a color change to blue. Siliciano remembers sitting at his desk,
talking with a visitor, when a graduate student burst in: “The wells are
turning blue!” He said, “It was a very strange moment, because it was a
confirmation of this hypothesis—so it was exciting—but it was also a disaster.
Everybody came to the same conclusion: that these cells persisted despite the
antiretroviral therapy.”
The Siliciano laboratory occupies the eighth floor of the Miller
Research Building, at the Johns Hopkins School of Medicine. The
twenty-six-person research team—technicians, students, fellows, and
faculty—works in an airy, open space and in a smaller Biosafety Level 3
facility on the north side of the building. There they handle the specimens of
their clinic’s H.I.V.-positive subjects and many more from labs like Deeks’s
worldwide. Inside a room with negative air pressure, researchers retrieve blood
samples from an incubator and place them in a laminar flow hood, which draws up
a stream of air. Nothing leaves the facility without being double-bagged and sterilized.
Much of the new AIDS research builds on the
Silicianos’ foundational discovery of H.I.V.’s hidden reservoirs. So does their
own work. Using potent chemicals, they have been able to draw H.I.V. out of its
hiding places in memory T cells, assess the reach of the virus within the body,
and begin to map where else it might be lodged.
Several years ago, they began looking at “blips,”
the small, sudden jumps in viral load that sometimes occur in the blood of HAART patients. Physicians had been concerned that
blips might be particles of virus that had become resistant toHAART and struck out on their own. The Silicianos
believed otherwise: that the viral particles were released by latently infected
cells that had become activated. They analyzed the blood of patients with blips
every two to three days over three to four months, and their hypothesis proved
correct: the virus had not become resistant to the drugs, but had been dormant
in its reservoir within memory T cells. It could be intermittently released from
the reservoir, even when the patient took antiretroviral drugs.
Although researchers were chastened by the realization that the drug
regimen was not itself a cure, they recently found three unusual cases that
were encouraging enough to make them keep trying. The first was that of Timothy
Ray Brown.
Brown is known as the Berlin patient, after the city where he became the
only person ever to have been cured of H.I.V. In 2006, more than a decade after
he discovered he was H.I.V.-positive, he was given an unrelated diagnosis of
acute myelogenous leukemia, a cancer of the bone marrow. After initial
treatment, the leukemia returned. Brown needed a bone-marrow transplant. His
hematologist, Gero Huetter, made the imaginative suggestion that they use a
donor with a genetic mutation that shuts down the protein CCR5, a doorway for
H.I.V. into helper T cells. On February 7, 2007, Brown received the transplant.
One year later, he underwent the procedure again, and by 2009 biopsies of
Brown’s brain, lymph nodes, and bowel showed that the virus had not returned,
and his T-cell count was back to normal.
Brown’s cure was spectacular, but difficult to
repeat. His doctor had twice destroyed all his native blood cells, with
radiation and chemotherapy, and twice rebuilt his immune system with
transplanted stem cells. It had been very dangerous and costly. Researchers
wondered if they could create a scaled-down version. In 2013, physicians at
Brigham and Women’s Hospital, in Boston, reported on the outcome of a study in
which two H.I.V.-positive men onHAART had received bone-marrow
transplants for lymphoma. Their marrow donors, unlike Brown’s, did not have the
CCR5 mutation, and their chemotherapy regimen was less intensive. HAART was stopped a few years after the
transplants, and the virus remained undetectable for months, but then
resurfaced.
This past July, results came in on the
third case. In 2010, a girl known as the Mississippi baby was born to an
H.I.V.-positive mother who had taken no antiretrovirals, and the baby had the
virus in her blood. Thirty hours after delivery, the newborn started on
antiretroviral therapy. Within weeks, the viral count fell below the limit of
detection. The baby was eighteen months old when the treatment was interrupted,
against medical advice. For two years, the girl’s blood showed no trace of the
virus, and researchers speculated that very earlyHAART might prevent the virus from
forming a dormant reservoir. Twenty-seven months after going off the drugs,
however, the child tested positive for the virus. Though researchers were
impressed that early intervention had temporarily banished H.I.V., she was not
cured.
In August, Janet and Robert Siliciano wrote about
the Brigham men and the Mississippi baby inScience, saying that the cases confirmed that
researchers were on the right path in attacking latent infection. The Berlin
patient was an even more compelling example. Karl Salzwedel, the chief of
Pathogenesis and Basic Research in the Division of AIDS at the National Institute of Allergy and
Infectious Diseases, told me that until Timothy Brown “it wasn’t really clear
how we would go about getting rid of the last bits of virus that remain in the
reservoir.” Brown’s case provided “a proof of concept: it may be possible to
eradicate latent H.I.V. from the body. It may be from a very risky and toxic
method, but it’s proof of concept nonetheless.”
The new centerpiece of the American effort to cure H.I.V. is the Martin
Delaney Collaboratories, funded by the N.I.H. Launched in 2011, the
collaborative was formulated as a way to link clinical labs, research
facilities, and pharmaceutical companies. Federal support was set at seventy
million dollars for the first five years, on the premise of coöperation and
open communication among all parties. Salzwedel told me that the N.I.H. funded
three applications. “Each was taking a different complementary approach to
trying to develop a strategy to eradicate H.I.V,” he said: enhancing the
patient’s immune system, manipulating the CCR5 gene, and destroying the
reservoirs themselves. They represented different responses to the Siliciano
thesis and to the lessons of Timothy Brown.
Mike McCune, the head of the Division of
Experimental Medicine at U.C.S.F., researches ways in which H.I.V. can be
eradicated by the body’s own immune system. He was prompted by an observation
made in the early days of the epidemic: that babies born to mothers with H.I.V.
become infected in utero only five to ten per cent of the time, even though
they are exposed to the virus throughout gestation. Recently, McCune and his
colleagues observed that the developing fetal immune system does not react
against maternal cells, which can easily cross the placenta and end up in fetal
tissues. Instead, the fetus generates specialized T cells that suppress
inflammatory responses against the mother, and that might also prevent
inflammatory responses against H.I.V., thereby blocking the rapid spread of the
virus in utero and sparing the child.
McCune has worked for many years with Steven Deeks
and the SCOPE Study. When I spoke with McCune
in San Francisco, he said, “There is a yin and yang of the immune system. We
are trying to recapitulate the orchestrated balance found in the fetus.” McCune
is now working on interventions that would prevent inflammation against H.I.V.
in the adult, hoping to partly mimic the balance found in utero. He’s also
developing methods that would allow the immune system to better recognize, and
destroy, the virus when it manifests itself. These studies are being carried
out on nonhuman primates, and may lead to human trials within a year or two.
In Seattle, a group headed by Hans-Peter Kiem and Keith Jerome is taking
a more futuristic approach. Using an enzyme called Zinc Finger Nuclease, they
are genetically altering blood and marrow stem cells so as to disable CCR5, the
doorway for infection in T cells. Researchers will modify the stem cells
outside the body, so that when the cells are returned some portion of the T
cells in the bloodstream will be resistant to H.I.V. infection. Over time, they
hope, those cells will propagate, and the patient will slowly build an immune
system that is resistant to the virus. Those patients might still have a small
reservoir of H.I.V., but their bodies would be able to regulate the infection.
The largest Collaboratory, with more than twenty members, is led by
David Margolis, at the University of North Carolina. Margolis, an
infectious-disease expert, is targeting the reservoirs directly. The idea,
which has come to be known as “shock and kill,” is to reactivate the dormant
virus, unmasking the cells that carry it, so that they can be destroyed. In 2012,
he published the results of a clinical trial of the drug Vorinostat, which was
originally developed for blood cancers of T cells, as a shock treatment. This
October, “shock and kill” was widely discussed when the Collaboratory teams
convened at the N.I.H., along with hundreds of other researchers, assorted
academics, and interested laypeople. Margolis and his group explored in their
talk new ways to shock the virus out of dormancy.
The killing stage is more challenging, because the shocked cells carry
few H.I.V. antigens, the toxic flags released by pathogenic particles and
recognized by the immune system prior to attack. One approach to the killing
strategy comes from an unusual type of H.I.V.-positive patient who may carry
the virus for decades yet seems not to be disturbed by it. Some of these
so-called “élite controllers” possess cytotoxic, or killer, T cells that attack
virus-producing cells. The objective is to make every H.I.V. patient into an
élite controller through “therapeutic vaccination,” enabling patients to
generate killer T cells on their own.
Researchers are also trying to switch off a
molecule called PD-1, which the body uses to restrain the immune system.
Deactivating PD-1 has worked in clinical studies with melanoma and lung-cancer
patients, and one patient seems to have been cured of hepatitis C by a single
infusion of a PD-1 blocker from Bristol-Myers Squibb.
Groups outside the Collaboratories who are testing
ways to cure AIDS share their results with the
N.I.H. teams. In parallel with the Seattle group, Carl June, the director of
translational research at the Abramson Cancer Center, at the University of
Pennsylvania, and his colleagues have used genetic engineering to close off the
CCR5 passageway. In the New England Journal of Medicine this past March, they reported on
their recent clinical trial, which showed that the modified T cells could
survive in people with H.I.V. for years. Similar work on knocking down CCR5 is
being done by Calimmune, a California-based company devoted to curing AIDS. (One of its founders is David Baltimore, who
received the Nobel Prize for the discovery of reverse transcriptase, a crucial
enzyme in retroviral reproduction.) Groups in Denmark and Spain have made
progress, too, and in 2012 researchers in France analyzed the Visconti study,
which had put the early intervention received by the Mississippi baby to a
formal test. A subset of fourteen H.I.V. patients had been treated within weeks
of their infection, and then HAART was interrupted. They remained
free of the virus for several years.
The fight against AIDS is following a trajectory similar to that of
the fight against many cancers. When I was growing up, in the nineteen-fifties,
childhood leukemia was nearly always fatal. Eventually, drugs were developed that
drove the cancer into remission for months or years, but it always came back.
In the nineteen-seventies, researchers discovered that leukemic cells lay
sleeping in the central nervous system, and developed targeted treatments that
could eliminate them. Today, childhood leukemia is cured in nine out of ten
cases.
This July, at the Twentieth International AIDS Conference, in Melbourne, Australia, Sharon
Lewin, an infectious-disease expert at Monash University, said, “We probably
are looking, at the moment, at trying to achieve long-term remission.” Most
experts agree that remission is feasible, and that, to some degree, we will be
able to wean patients off lifelong therapies.
Even the most cautious AIDS researchers place remission along a
continuum, with a cure at the end. Robert Siliciano told me, “The first goal is
to reduce the reservoir. And this is not just for the individual but also has a
public health consequence.” For however long a person is off HAART, doctors would be able to divert resources to patients
who still needed treatment.
David Margolis believes that his “shock and kill” strategy will work,
but that it could take ten to twenty years. The Silicianos agree that more
research is needed. “Shock and kill,” they said, will require more than a single
drug like Vorinostat. And the optimal regimen can’t be identified until it’s
clear precisely how much latent virus the body contains. The Silicianos have
not yet developed a truly accurate measure. Only by following people who have
been off all drugs for years would it be clear that a cure had been found. “The
more we learn, the more questions there are to answer,” Janet told me.
Still, the questions that have been answered
astonish AIDS scientists. At U.C.L.A. during
the brutal first years, I never would have imagined that future patients would
live into their eighties. A fatal disease has been tamed into a chronic
condition. The next step is to find a cure. Scientists are innately cautious,
and AIDS researchers have learned humility
over the years. Science operates around a core of uncertainty, within which lie
setbacks, but also hope.
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