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Reservoir explorers find extra HIV/SIV pond

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Quinn Eastman

Lymph node of someone living with HIV and treated with antiviral drugs. Red indicates HIV proviral DNA, green is CTLA4 and blue is PD1.

From McGary et al Immunity (2017).

Scientists at Yerkes National Primate Research Center, Emory University have identified an additional part of the HIV reservoir, immune cells that survive and harbor the virus despite long-term treatment with antiviral drugs.

Their findings were published online on Tuesday, October 17 in Immunity.

The cells display a molecule called CTLA4, the target of an FDA-approved cancer immunotherapy drug, ipilimumab. This information should help those trying to eradicate HIV from the body.

Researchers led by Mirko Paiardini, PhD, infected macaques with HIV's relative SIV and treated them with standard antiviral drugs similar to what humans receive for HIV. At the time of analysis, almost all the animals (8 out of 9) showed undetectable SIV in their blood. The team probed for CD4+ memory T cells, which are known to shelter persistent virus.

"We found that a certain group of memory CD4+ T cells displaying CTLA4, but not another co-inhibitor receptor called PD1, harbor viral DNA at higher frequencies than other groups of memory CD4+ T cells," Paiardini says. "These cells can be found in multiple tissues, such as lymph node, spleen, gut and bone marrow, and contain replication-competent and infectious virus."

Paiardini is associate professor of pathology and laboratory medicine at Emory University School of Medicine and Yerkes National Primate Research Center and part of Emory Vaccine Center. Guido Silvestri, MD, division chief of microbiology and immunology at Yerkes and a Georgia Research Eminent Scholar, is a co-author. 

The Yerkes team worked with researchers at NCI/Leidos Frederick led by Jacob Estes, PhD, using a technique called "DNAscope", to visualize latently infected cells in lymph nodes. Previous research had shown that HIV-infected cells persist in regions of the lymph nodes called B cell follicles. The newly identified group of infected cells is found outside the B cell follicles.

Working in close collaboration with Rafick Sekaly, PhD, at Case Western Reserve University, the research team also showed that the CTLA4-positive PD1-negative cells have the characteristics of regulatory T cells, whose job is to put a brake on the immune system and prevent it from getting too excited.

"It provides a strong rationale for targeting these cells," Paiardini says. "Depleting latently infected T-regs can not only reduce the reservoir, but also induce a stronger antiviral immune response."

The researchers also worked with Vincent Marconi, MD, a physician treating HIV in Atlanta, to confirm that similar cells were present in human lymph nodes. The human samples came from six HIV-positive individuals who had been on antiviral drugs for an average of three years.

Based on the team's findings, CTLA-4 should be considered as an additional target when designing immunotherapies aimed at purging the viral reservoir, Paiardini says.

The co-first authors of the paper are Colleen McGary, PhD, former Immunology and Molecular Pathogenesis graduate student, Justin Harper, PhD, Yerkes research supervisor, Luca Micci, PhD, Yerkes postdoctoral fellow and Claire Deleage, PhD, postdoctoral fellow at NCI Frederick. 

The research was supported by the National Institute of Allergy and Infectious Diseases (AI104278, AI116379, AI116171, AI110334, P30AI50409), amfAR/the Foundation for AIDS Research (109354-59-RGRL), the NIH Director's Office of Research Infrastructure Programs (Primate centers: P51OD011132), and the National Cancer Institute (Contract HHSN261200800001E).

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