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HIV researchers target viral reservoir

July 26, 2012 This article courtesy of Nature News.

While a cure for HIV remains elusive, new research suggests that eliminating HIV from the reservoirs where the virus persists is possible.

With the success of antiretroviral therapy and an ever-increasing number of drugs to treat HIV, some researchers are focusing their attention on a loftier goal — a cure. That means targeting viral reservoirs, the long-lived cells where HIV lies dormant. Eliminating these reservoirs isn’t proving easy, but recent research offers glimmers of hope that it will be possible.

The strongest proof that HIV can be cured comes from the case of Timothy Brown, who was infected with HIV until he received a stem-cell transplant in 2006 to treat leukemia [1]. Brown has remained free of HIV since then. Brown’s transplant worked, in part, because the donor lacked a key receptor that HIV needs to enter cells. But some researchers are exploring the idea that stem cell transplants may eliminate the virus even if the donors don’t have that rare genetic deletion.

At the International AIDS Conference in Washington DC on Thursday, Timothy Henrich, an infectious disease physician at Brigham and Women’s hospital in Boston, Massachusetts, reported on two HIV-infected men who received stem cell transplants without the deletion. The transplants did not immediately eliminate the men’s infected immune cells. Yet, eight and nine months later, the men had no evidence of HIV in their blood.

The men became virus free at about the same time that the donor cells became predominant, and both men developed graft-versus-host disease, a condition in which donor immune cells attack the transplant patient’s cells. Henrich and his colleagues speculate that the antiretrovirals the men took during and after the transplant protected the donor cells from infection. These healthy donor cells then destroyed the infected cells, leaving the men free of virus.

“Theoretically they could be cured because the immune system was rebuilt under the coverage of antiviral therapy,” says Steven Deeks, an HIV researcher at the University of California, San Francisco, who wasn’t involved in the research. The ultimate test, however, will be to see whether they remain HIV-free when they stop taking antiretroviral medicines. Henrich is working with the patients and their physicians to figure out whether that is feasible.

Flushing out the virus Bone marrow transplants wipe out the viral reservoir by obliterating the entire immune system and replacing it with a healthy one, but they’re too risky to be used on people who don’t have a life-threatening illness. “This is not scalable or affordable or reasonable or ethical in anyone else,” Deeks says.

A more palatable tactic would be to purge the virus from its hiding spots, primarily long-lived memory cells. A paper published Wednesday in Nature provides the first human evidence that this may be possible[2]. David Margolis, an HIV expert at the University of North Carolina’s Center for Infectious Diseases in Chapel Hill, and colleagues administered a cancer drug called vorinostat to eight people in an attempt to coax dormant HIV out of hiding. A single dose of the medicine, which belongs to a class of drugs known to affect gene expression, produced a 4.5-fold increase in HIV RNA expression. It’s still unclear whether this increased expression will lead to the destruction of infected cells and shrink the reservoir. “But it's a positive signal,” says Nicolas Chomont, an HIV researcher at the Vaccine & Gene Therapy Institute of Florida.

But eliminating the viral reservoir may not be necessary in every case. In 2010, a team of French researchers reported that they had identified a small group of individuals who began antiretroviral therapy soon after infection, then stopped taking the drugs after several years of treatment[3]. Since stopping treatment, these individuals have been able to control the virus naturally, some for as long as ten years.

Unlike so-called “elite controllers”, who carry protective alleles, this group doesn’t seem to have any protective genetic component. At the conference, the team presented an in-depth look at the viral reservoirs of eight people in this group. The researchers found that the virus seems to reside largely in shorter-lived memory cells, not in the longer-lived cells. Asier Saez-Cirion, an HIV researcher at Institut Pasteur in Paris, says that may explain why, in four people, the reservoir has shrunk over time. But whether this decrease is connected to their ability to control the infection is not yet clear. Early, prolonged treatment is key, but isn’t enough. Just 5 to 15% of those who receive early treatment and then stop therapy are able to control their infection, Saez-Cirion says.

“I think [these individuals] are fascinating,” Chomont says. “They have something that makes them able to control the virus.” The trick will be to identify what that is, he adds, and then find a way to reproduce it.

While many questions remain for all these researchers, optimism abounds. “This is very similar to the dawn of the antiretroviral era in the mid-80s,” Deeks says. “Every time we turn around there's something that we learn that opens up new avenues and makes people optimistic.”


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