UCSF/amfAR HIV Cure Summit Reviews Progress in Cure-Related Research

alt

Researchers at the amfAR Institute for HIV Cure Research at the University of California at San Francisco (UCSF) presented an update on their latest cure-related work at a World AIDS Day summit on December 1. This multidisciplinary effort aims to understand HIV reservoirs within the body and ultimately to control or eliminate the virus.

While complete eradication of HIV from the body seems like a distant prospect, a more feasible goal is a so-called functional cure. This would "allow an HIV-infected person to live a full life without having to take medicines, without having to worry about transmitting the virus, and without having to suffer any complications from HIV infection," said Paul Volberding, director of the UCSF AIDS Research Institute.

The institute was established last year with a $20 million grant from amfAR, the Foundation for AIDS Research. Finding a cure is not a short-term effort, acknowledged amfAR CEO Kevin Frost. "But that's the history of medicine -- taking things that are dangerous, complicated, and expensive and making them safer, simpler, and cheaper."

The Challenge of a Cure

Combination antiretroviral therapy (ART), which debuted in the mid-1990s, has made HIV a chronic manageable disease for most people with access to treatment, often using a single once-daily pill.

But current treatments are not a cure. HIV's genetic material (known as a provirus) remains hidden in inactive immune cells. If antiretroviral drugs are stopped, the latent virus almost always resumes replicating and attacking T-cells. Even during treatment, researchers now recognize that inactive HIV can cause inflammation that contributes to conditions such as cardiovascular disease and cancer.

Researchers have tried various approaches to curing HIV, including very early antiretroviral therapy, gene therapy or stem cell transplants that protect T-cells from infection, the "shock and kill" strategy that aims to flush the virus out of hiding and destroy it, and strengthening natural immune responses against the virus.

But these efforts have generally not led to long-term control of the virus. Only one person -- Timothy Ray Brown, known as the Berlin Patient -- appears to have been truly cured, with no detectable HIV in his body 9 years after receiving bone marrow transplants from a donor with the natural CCR5-delta-32 mutation that makes T-cells resistant to infection.

A pair of other HIV-positive bone marrow transplant patients in Boston, who received normal, non-mutated stem cells, managed to hold off viral rebound for a while after stopping antiretrovirals -- 8 months in one case -- but eventually the virus returned. Extensive studies of these patients suggest that having even a single remaining latently infected cell in the reservoir may be enough to rekindle HIV replication and all its detrimental consequences.

The Boston patients showed us that "the virus was lurking all along" but we didn't have sensitive enough methods to detect it, said UCSF associate professor Satish Pillai, who is working on new tools including radioactive labeling that lights up HIV-infected cells. "We have a lot of very expensive technologies that all do slightly different things and tell different stories, but we don't really know if any of these are telling us the absolute truth."

Understanding the Viral Reservoir

Much of the cure institute's research involves figuring out ways to more accurately measure the viral reservoir, determine whether residual virus is "replication-competent," or able to reproduce and infect new cells, and whether experimental therapies are having an effect on the reservoir.

A new wrinkle in cure research, according to Pillai, is the growing understanding that even defective latent HIV that is not able to produce infectious new viruses may still spit out viral proteins that can trigger an inflammatory immune response.

"We're probably going to have to figure out what to do with this class of viral genomes as well," Pillai said.

Only about 1% to 2% of CD4 T-cells are circulating in the blood at any given time, while the majority live in tissues of the body such as the gut and lymph nodes, explained UCSF associate professor Peter Hunt. Cells in tissues may be different from those in the blood and may respond differently to experimental therapies, which may not be able to reach the sequestered specialized T-cells that are most likely to harbor HIV.

"If we're only getting peripheral blood draws, we're never going to see these specialized subsets of cells, said Hunt, who studies HIV-infected cells in tissue biopsy samples.

Furthermore, just 1 out of every million T-cells in the body is latently infected with HIV.

"Our challenge is to study those 4 cells amongst the millions and millions of other cells, and further to attack and kills those cells without harming any of the other cells," said Warner Greene, director of UCSF's Gladstone Institute of Virology and Immunology.

Researchers in San Francisco have been "very fortunate to have many volunteers from the community who are willing to share their blood with us through leukapheresis," a procedure that extracts specific types of cell from large volumes of blood, Greene added. "It is these types of precious, precious cells that form the gold standard for our studies."

UCSF professor Steven Deeks discussed the challenges of applying the work of researchers in the laboratory to the community of people with HIV in the clinic, and vice versa.

"We almost invariably find out things we didn’t think would happen that require explanation, and the institute allows us to seamlessly take observations from clinical trials right back into the lab to answer those questions as they come up in real time," Deeks said. "There's a synergistic relationship between the community, the clinicians, and the basic scientists which I honestly think does not work as well anywhere else."

Testing new approaches will eventually require study participants to temporarily interrupt antiretroviral treatment with close monitoring to see if the virus bounces back, because we do not yet know how to measure the reservoir directly, he said.

A study starting in early 2017 will test GS-9620, a TLR7 agonist from Gilead Sciences that turns on immune responses. Researchers will later test a TLR9 drug as a backup plan, and therapeutic vaccine trials will probably start in about a year, according to Deeks.

"I do not think we're going to cure people with a single drug…it's going to require a combination approach." Deeks predicted. "People often ask me when we'll cure HIV. I have no idea, but I think we're going to have a combination regimen that's viable and testable" by the end of the first 5-year funding cycle.

"No one in 1993 had any idea we'd be actually able to control the virus, but yet three years later we did," Deeks continued. "Where we are with [cure] science is like where we were [with treatment] in the late 1980s and early '90s. We're beginning to have a vision of what a combination regimen might look like and have started working in that direction."

12/21/16

Source

HIV Cure Summit 2016. amfAR Institute for HIV Cure Research. December 1, 2016.