amfAR HIV Cure Summit: Recording and Eliminating Viral Reservoirs

On Monday, November 17 at 7 World Trade Center in New York City, Timothy Henrich, MD, of Harvard Medical School and Brigham and Women's Hospital and Steven Deeks, MD, of University of California, San Francisco, shared their research on recording how much HIV virus hidden "viral reservoirs" contain, and finding ways to eliminate this virus.

"We often talk about transplantation as the only cure, but what exactly is going on?" asked Henrich. "The person undergoing transplanting gets a mixture of chemotherapy plus irradiation, and try to eliminate as many of those cancer cells as possible. We call this conditioning. It's quite toxic and can reduce the number of cells in the body quite drastically. The ones that are left over can be sickened by this conditioning regimen."

After this conditioning, they introduce stem cells from a matched donor, and over a couple of months to a year, the donor cells identify sickened cells and clear them out. Eventually, you'll only have donor cells.

With HIV infection, the virus uses the CCR5 cells as a sort of a doorknob, to get in and infect healthy cells. In the case of the Berlin Patient cure, a donor was found with the CCR5 Delta 32 mutation that lacks this receptor, so HIV just can't get in.

"That's exactly what happened with the Berlin patient," said Henrich. "Cells did not express functional CCR5 on their surface, and his strain of HIV is not able to get into those donor cells, which have gradually replaced his own cells over time. So then the question is, 'Can we do this without the Delta32 mutation?"

Only 4-10 percent of all people have this mutation. Because it's so difficult to find, doctors tried to see if it was sufficient to protect the donor cells by keeping patients on antiretrovirals (ARVs) during and after the transplant. Some are also using umbilical cord cells, which are a bit more forgiving of mismatches, and increase the chances of finding donors.

Early excitement led to disappointment when two men who underwent this therapy were initially free of HIV in their blood and gut, with a 1,000-10,000 fold reduction in their HIV reservoir. But it wasn't enough to stop HIV. Years after the transplant, they were removed from ARVs, and within three to eight months, the HIV was back.

"Our other patient went for eight months without detectable HIV either in the cells or the bloodstream; we just weren't able to find it," said Henrich. "This patient told me he felt for 8 months of his life that he was HIV-negative. For him, that was a cure. Now the question is, 'How low do we actually need to go to cure HIV?'"

And in Mississippi, a baby infected with HIV prior to their birth was put on ARVs early, and the HIV went away. The child didn't return for treatment until several years later, and doctors couldn't find the HIV. But after two years without ARVs, it did return.

Now, Henrich and his team are trying to develop more sensitive assays to find out where the HIV is hiding. One method is by taking a patient's blood out via leukapheresis and siphon out the lymphocytes that harbor HIV, then to put it back in the body. Another is by infusing patients' cells into humanized mice, then waiting about 12 weeks for the cells to begin producing the virus.

"Lo and behold, early data shows that mice models are more sensitive than petri dishes," said Henrich. "The hope is that once we develop more sensitive techniques, we can apply it to patients like Brown and the Mississippi patient to see if we can find HIV."

Eliminating the Virus

At University of California, San Francisco, Dr. Deeks is working on two routes to a cure: A functional cure, where HIV persists but is in remission; and a sterilizing cure, where doctors go in and remove HIV via a "shock and kill" gene therapy.

In his effort to clear out the virus, Deeks is looking at preventing latent reservoirs by giving someone ARVs before they are exposed (or within 24 hours of exposure), such as PrEP via Truvada, or by pounding it with ARVs for the first year or so, such as in the case of the Mississippi baby.

"Get drugs into a person early, and you can avoid a latent reservoir," said Deeks.

In San Francisco, some high-risk gay men were put on PrEP to prevent infection. Some had already been HIV-positive for a few days, but after a year and a half of therapy, they couldn't find the virus anywhere. Deeks said they were sending their blood to infect mice models and see.

The other strategy is to "shock and kill" the virus. Deeks said that patients are given two doses of Romidepsin, so the virus comes out of hiding. Then the antiretrovirals can hit it. They are also working on using the anti-alcoholic drug Antabuse to shock it out of hiding. The drug is effective, with no toxicity (as long as patients don't drink alcohol).

Other promising solutions include vaccine researcher Louis Picker's move to take cytomegalovirus (CMV) and engineer it as a live HIV/SIV vaccine. They put it in monkeys to create "effector memory" T-cells that targeted the SIV, and the monkeys were cured.

And in France, the VISCONTI cohort found a functional cure when they started ART within the first few weeks of infection, and then stopped the treatment. Seven years later, they still have detectable HIV in their blood, but after seven years without ART, they don't show any signs of disease progression.

"The vaccine and cure worlds are merging, thanks to CMV and natural antibodies," said Deeks. "We think if you block these T-cells, you can cure HIV."

In the case of the Berlin patient, the cell and gene therapy route has found success, as Timothy Brown has been HIV-negative for more than five years. Biopsies, lumbar punctures and blood draws were sent around the world, and as Deeks noted, "We all concluded at the end of the day that there was no HIV left."

"Curing HIV is an ambitious, but feasible goal," said Deeks. "We need nimble funding that can move with 'high-risk' science, multidisciplinary research, input from academia, biotech and pharmaceuticals, and a long-term commitment of more than five years."

With amfAR's ARCHE program, they may just find the tools they need to finally find a cure for HIV.