AIDS research anticipates a ‘functional cure’

July 26, 2012

Two studies presented at the 19th International AIDS Conference and one published this week in a journal have given researchers renewed hope that a cure for AIDS may be possible.

None of the strategies are easy, proved or ready for prime time. But all involve procedures or drugs that are already in use and are able to be deployed widely if further research bears out the early findings.

“Today might be considered a day when the research agenda moves from basic science and the lab into the clinic,” said Steven G. Deeks, an AIDS researcher at the University of California at San Francisco who is not directly involved in the studies. “It is an absolutely critical advancement.”

One strategy involves waking up sleeping cells infected with HIV so they can then be killed. Another requires treating people with HIV drugs immediately after infection, something that has been tried previously without the dramatic effects described on Thursday. The third strategy requires stem cell transplantation, a difficult and expensive procedure.

The outcomes described by the researchers do not constitute cures in the usual sense. In some patients, HIV remained detectable in some cells. In others, whether it remained after treatment was uncertain. But that may not make a difference. Most experts say a “functional cure” — in which the virus persists but the body controls it — would be a major breakthrough.

The researchers steered clear of using the word “cure.”

“We are very careful about what we say,” said David Margolis of the University of North Carolina. “But you cannot argue about the value of the goal.”

Curing HIV infection is difficult because in certain types of human cells the virus stitches itself into the infected person’s DNA, becoming in effect a part of the patient’s “self.” To make matters worse, those cells survive for decades. But like Sleeping Beauty, they can awaken with the right stimulation and live out their lives, which in their case means making HIV that attacks other cells and perpetuates the infection. A true cure would have to target those sleeping cells, probably by waking them up in order to kill them.

Only one person is believed to have been cured of HIV infection. He is Timothy Brown, an American who was treated in Germany and is known as “the Berlin patient.” He received a stem cell transplant for leukemia, and his forward-thinking physician, Gero Hutter, chose for a donor someone with a rare mutation whose cells couldn’t be infected with HIV. When Brown recovered, his body contained no detectable virus.

That surprising finding reignited cure research, which had been dormant after unsuccessful attempts in the 1990s.

In a session at the AIDS conference on Thursday, Timothy J. Henrich and Daniel R. Kuritzkes of Harvard Medical School described the experience of two people with HIV infection who, like Brown, had undergone stem cell transplants. In their cases, it was because of lymphoma, which like leukemia is also a blood cell cancer. The chemotherapy they received was less aggressive than Brown’s and more of their immune cells remained. The transplanted cells apparently hunted down those cells — some of which were infected with HIV — and killed them in a reaction known as “graft vs. host disease.”

In one patient, no HIV could be grown out of the blood 31 / 2 years later, and in the other almost two years later.

Asked by one of his listeners why the research team didn’t term the results “eradication,” Henrich said: “We didn’t want to overplay our hand. It is possible there is other residual HIV material somewhere.”

In the second presentation, Charline Bacchus and Asier Saez Cirion of the Pasteur Institute in France described 14 patients who started antiretroviral therapy — the combinations of three drugs that is the standard treatment for HIV — within weeks of becoming infected. They took the medicines for an average of three years and then stopped.

Today, after being off them for an average of six years, these patients have little or no HIV detectable in their blood. They do have virus in some sleeping immune cells, but they are not of the type that live for decades. That gives the researchers hope that they might eventually die out.

What explains these patients?

One theory is that treatment was started before there was time for the virus to seed itself widely in many tissues. It’s possible they may have a genetic predisposition for controlling the infection. However, they do not have the rare constellation of genes seen in people who become infected and never need to take a pill — a group known as “elite controllers.”

The search is on for more patients like them.

The third hopeful development was published this week in Nature. The strategy is known as “shock and kill.” Margolis and his team at UNC demonstrated they can “shock” sleeping cells awake. Whether those cells can be killed remains to be seen.

In its experiment, the team gave a one-time dose of the cancer drug vorinostat to eight patients on antiretroviral therapy. Within six hours, HIV from the sleeping cells could be detected.

The researchers don’t know if all HIV patients will respond to vorinostat, and are uncertain of what the optimal dose might be. But Deeks said that of the three studies presented, Margolis’s work is the most promising — a “landmark study” that provides a proof of concept that an entirely new approach to managing HIV infection may be possible.

He compared the significance of vorinostat’s discovery to the anti-HIV drug AZT, the first drug used to treat HIV infection and the precursor to hundreds of antiretrovirals on the market today.

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