New Hope of a Cure for H.I.V.-Update

Heidi Schumann for The New York Times

VIRUS-FREE Timothy Brown of San Francisco had two bone-marrow
transplants to treat leukemia, and H.I.V. can no longer be detected in
his body.

By ANDREW POLLACK
Published: November 28, 2011

Medical researchers are again in pursuit of a goal they had all but
abandoned: curing AIDS.

Until recently, the possibility seemed little more than wishful
thinking. But the experiences of two patients now suggest to many
scientists that it may be achievable.

One man, the so-called Berlin patient, apparently has cleared his
H.I.V. infection, albeit by arduous bone marrow transplants.

More recently, a 50-year-old man in Trenton underwent a far less
difficult gene therapy procedure. While he was not cured, his body was
able to briefly control the virus after he stopped taking the usual
antiviral drugs, something that is highly unusual.

“It’s hard to understate how the scientific community has swung in its
thinking about the possibility that we can do this,” said Kevin Frost,
chief executive of the Foundation for Aids Research, a nonprofit
group. “Cure, in the context of H.I.V., had become almost a
four-letter word.”

There were attempts in the past to cure the disease, but most experts
thought it more feasible to focus on prevention and treatment.

The push for a cure might seem even less urgent now that antiviral
drugs have turned H.I.V. infection from a near-certain death sentence
to a chronic disease for many people.

But the drugs are not available to everyone, and they do not eliminate
the infection. Even if undetectable in the blood, the human
immunodeficiency virus lurks quietly in the body. If a patient stops
taking the drugs, the virus almost always comes roaring back.

So people with H.I.V. now must take drugs every day for life, which
some researchers say is not a sustainable solution for tens of
millions of infected people.

“I don’t think the world has the resources to deliver these drugs to
everyone who needs them for decades,” said Dr. Steven Deeks, professor
of medicine at the University of California, San Francisco.

A cure may be the only realistic solution. The National Institute of
Allergy and Infectious Diseases, which says a cure is one of its top
priorities, this year awarded grants that could total $70 million over
five years to three research teams in pursuit of that goal. More
grants are coming.

California’s stem-cell agency has committed a total of $38 million to
three projects intended to find a cure. Companies like Merck, Gilead
Sciences, Sangamo BioSciences and Calimmune have begun research.

It will be years before there is a cure, if there ever is, though some
scientists are more optimistic than others.

“I think we are much closer to a cure than we are to a vaccine,” said
Rafick-Pierre Sékaly, scientific director of the Vaccine and Gene
Therapy Institute of Florida.

There are two main approaches. One is a so-called sterilizing cure —
the eradication of H.I.V. from the body. The other, a functional cure,
would not eliminate the virus but would allow a person to remain
healthy without antiviral drugs.

Hope for a cure was raised in part by the experience of the Berlin
patient, an American named Timothy Brown who had both H.I.V. and
leukemia.

In 2007 and 2008, while living in Berlin, Mr. Brown received two
bone-marrow transplants to treat his leukemia. The donor was among the
1 percent of Northern Europeans naturally resistant to H.I.V.
infection because they lack CCR5, a protein on the surface of immune
cells that the virus uses as an entry portal.

With his own immune system replaced by one resistant to infection, Mr.
Brown, 45, who now lives in San Francisco, has apparently been free of
the virus for about four years. But bone marrow transplants are
grueling, risky and expensive. Moreover, it is hard enough to find an
immunologically matching donor, let alone one with mutations in both
copies of the CCR5 gene.

So scientists are trying to modify a patient’s own immune cells to
make them resistant to infection by eliminating CCR5.

This is what was done with the Trenton patient. Some of the man’s
white blood cells were removed from his body and treated with a gene
therapy developed by Sangamo BioSciences. The therapy induced the
cells to produce proteins called zinc-finger nucleases that can
disrupt the CCR5 gene.

The treated cells were then infused back into the man’s body. One
month later, as part of the experiment, the man stopped taking his
antiviral drugs for 12 weeks.

As expected, the amount of H.I.V. in his blood shot up. But then it
fell back to an undetectable level just before the end of the 12-week
period. The patient’s immune cell counts also shot up.

“I felt like Superman,” he said in an interview, though this could
have been partly because he stopped taking the antiviral drugs that
had caused fatigue.

The man spoke on the condition of anonymity because he has not told
many friends and relatives that he has H.I.V.

Dr. Pablo Tebas, a professor at the University of Pennsylvania who
treated the man, said, “It is only one individual, but it is a
remarkable result.” Some outside experts were cautious. “At 12 weeks,
you can’t say that this therapy works and the patient is controlling
it by himself,” said Dr. Jeffrey Laurence, director of the AIDS
research laboratory at Weill Cornell Medical College.

Nevertheless, he called the results “amazing.”

The gene therapy did not work so well for five other patients,
according to results presented in September at the Interscience
Conference on Antimicrobial Agents and Chemotherapy.

Researchers hypothesize that the Trenton patient did better because he
had an inherited mutation in one of his two CCR5 genes, making the job
easier for the gene therapy. Up to 13.5 percent of his CD4 cells, the
main immune cells infected by H.I.V., were missing both copies of the
CCR5 gene after the treatment. That is about twice as much as observed
in the other patients.

Still, a vast majority of his CD4 cells were not genetically altered
and remained susceptible to infection, making it puzzling that the
therapy worked at all.

Some scientists said this suggested that freeing as little as 10
percent of CD4 cells from infection might somehow allow the immune
system to control the virus. Researchers are contemplating how to
increase the percentage of CCR5-deficient cells in patients who lack
the Trenton man’s genetic mutation.

A team from the City of Hope and the University of Southern
California, and another team from Calimmune and the University of
California, Los Angeles, are working on disabling the CCR5 genes in
blood stem cells. That would potentially make the entire immune system
permanently resistant to infection, though patients would require a
stem cell transplant.

Detractors say a functional cure would not offer much beyond existing
drug therapy.

“Any approach that is going to require genetic engineering on a
patient-by-patient basis is just utterly unrealistic in terms of the
global epidemic,” said Dr. Robert Siliciano, professor of medicine at
Johns Hopkins.

Dr. David Margolis, of the University of North Carolina, said, “Some
sort of gene therapy like that, that suppresses viral load to some
extent for some period of time, is not a lot different from taking one
pill once a day.”

Dr. Siliciano and Dr. Margolis are trying to eradicate the virus from the body.

H.I.V. can lie dormant for years. One refuge is the resting memory
T-cells, which are the long-lived cells that “remember” exposure to a
pathogen and help mount an immune response if the same germ invades
the body years later.

The hope is that a drug can activate the latent virus and flush it out
of its hiding places. One candidate, now being tested in a small
clinical trial, is vorinostat, sold by Merck under the name Zolinza to
treat a rare cancer.

Vorinostat reverses a mechanism that cells use to silence genes.
H.I.V. is believed to take advantage of this mechanism to become
dormant.

Another candidate, now being tested in primates, is an antibody
developed by Merck to block a protein called PD-1.

But the sterilizing cure would also be challenging. “The virus is in
the brain, it’s in the heart, it’s in the kidney, it’s in lots of
different tissues,” said Dr. Jay Levy, a virologist at the University
of California, San Francisco.

Vorinostat might activate not only the virus, but also genes that are
supposed to remain silenced, causing side effects. Activating too many
resting memory T-cells could lead to a dangerous immune system
overreaction.

And once the cells and viruses are awakened, they would have to be
killed, not just allowed to run amok.

Any attempt at a cure must be very safe, because most patients already
do well on antiviral drugs, said Mark Harrington, executive director
of the Treatment Action Group, an AIDS research policy organization.

Still, Mr. Brown, the Berlin patient, is now giving speeches urging
work on a cure. And the Trenton patient, who is back on antiviral
drugs, said he wants to be treated again.

“I feel like Oliver Twist in the orphanage,” he said, “going up with
the empty bowl in his hand saying, ‘Please, may I have more, sir?’ ”