Targeting HIV Reservoirs

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Hiding Place
One focus of the amfAR 2016 CURE Summit targeted HIV reservoirs
by Jeannie Wraight

This year, amfAR marked World AIDS Day with the 2016 HIV Cure Summit in San Francisco, California. The summit provided an overview of our current understandings in HIV cure research and provided us with a rundown of the goals and ongoing research of the amfAR Institute for HIV Cure Research.

The Cure Institute was formed in November of 2015 with the goal of exploring some fundamental questions that may lead to the discovery of a functional and/or an eradication cure of HIV. They intend to develop the “scientific basis of a cure for HIV by the end of 2020.” The Cure Institute made its home on the campus of the University of California San Francisco (UCSF) with a $20 million a year commitment by amfAR for five years—a total of $100 million dollars.

So, what exactly does the “scientific basis of a cure” entail? Currently, the main barrier to “curing HIV” is believed to be HIV viral reservoirs. The Cure Institute is dedicated to understanding and eradicating the HIV reservoir. This will be done through numerous projects to enhance immune response, to reverse latency (activate the resting cells harboring HIV and to kill off these cells) and to control the reservoirs after clearance.

Working in teams and with industry partners (including Gilead, UC Berkley, and the Gladstone Institute), researchers at the Institute are centering on four main projects, the acronym for which is CURE:
Chart the location of reservoirs
Understand how reservoirs are established and persist
Record size of reservoirs
Eliminate reservoirs

Research will focus on finding where the reservoirs are, how big they are, what latent cells HIV resides in, how to identify these cells, how to activate and then eliminate them, and then how to prevent more reservoirs from being established.

Research at the Institute has thus far found some interesting results. One main issue is finding out exactly where the reservoirs are. The viral reservoir is not located in one singular place, but found in cells throughout the body including the gut, lymph nodes, and tissues. They are also found in several different cells, but primarily in CD4 cells.

Dr. Peter Hunt, Associate Professor of Medicine at the HIV/AIDS Division, UCSF, gave an interesting talk on the progress that has been made so far at the Institute.

He discussed charting reservoirs in tissue. Dr. Hunt explained that most of our CD4 cells reside in the lymph nodes, spleen, and the lining of the gut, with only one to two percent of our total CD4s circulating in the blood at any given time. Most are in the gut, spleen, and lymph nodes. There are ten times more cells infected with HIV in the gut than in the blood.

Some of the HIV-infected cells that are not found in blood behave very differently than peripheral cells and may respond differently to interventions to activate or kill them, so identifying and understanding them is very important.

T follicular cells (Tfcs) reside in the lymph node and are a major reservoir for HIV. They live in B Cell follicles. B Cells are responsible for making antibodies, and Tfcs help them. Tfcs are the main target of HIV in the lymph node and produce most of the replicating virus in the lymph in a person not on ARVs. In these follicles, Tfcs are protected from cells that would normally attempt to kill HIV-infected cells, like cytotoxic CD8 and natural killer cells. This may also make them hard to kill with immune-based therapies, one strategy for reducing the viral reservoir.

Tissue Memory Resident Cells (TMRs) are another reservoir cell that may be difficult to kill as they are able to hide from the immune system. They’re located in the gut and tissue but not the blood, so they cannot be seen through normal blood draws.

By measuring the amount of HIV in Tfcs and TMRs through gut and lymph node biopsies, researchers at the Cure Institute will explore several questions that could lead to a better understanding of how to rid the body of these latently infected cells. They will try to determine if the amount of HIV in these cells can predict how long it will take for viral rebound during a treatment interruption. They will also evaluate different shock-and-kill therapies on these cells.

Another team at the Institute is focused on ways to identify which cells harbor HIV. Currently only a few markers have been identified (Exhaustion markers: PD-1, LAG-3, TIGIT) and these are not fully reliable. These researchers are looking for signatures which could be used to identify cells with latent HIV through total body imaging.

As the research at the amfAR-sponsored Cure Center at USCF continues, our knowledge of HIV reservoirs grows, getting us closer and closer to first a functional and then hopefully, an eradication cure of HIV.


Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.