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UNC School of Medicine research led by Nilu Goonetilleke, PhD, reveal how HIV-1-specific immune cells can recognize viral particles that have the capacity to rebound following interruptions to antiretroviral therapy. The findings have implications for new treatment strategies.

CHAPEL HILL, NC – October 6, 2020 – Immune cells that can recognize residual HIV-infected cells in people living with HIV (PLWH) who take antiretroviral therapy (ART) remain active for years, according to a new study led by UNC School of Medicine researchers.

The findings, published in eLife, also suggest the majority of these CD8+ T cells immune cells should have the capacity to detect the HIV-infected cells that drive HIV-1 rebound following interruptions to treatment. This insight could contribute to the development of new curative strategies against HIV infection.

This work was led by senior author Nilu Goonetilleke, PhD, assistant professor in the UNC Department of Microbiology and Immunology and member of the UNC HIV Cure Center, and first author Joanna Warren, PhD, a postdoctoral researcher at UNC-Chapel Hill.

ART has transformed HIV-1 from a fatal disease to a chronic condition. However, individuals must be on the therapy for the rest of their lives because stopping treatment often allows the virus to rebound within weeks. This rebound results from cells harboring HIV-1 DNA that is integrated into the human genome in a state often described as “latency.”

“While more than 95% of pro-viral DNA is unable to replicate and reactivate HIV-1, the remaining fraction that we define in our study as the ‘HIV-1 reservoir’ maintains its ability to produce infectious virus particles and cause viral rebound,” Warren said. “The largest and most well-characterized HIV-1 reservoir resides in ‘resting’ CD4+ T cells, which circulate in the blood and are long-lived.”

There are a couple of strategies under investigation to allow people with HIV-1 to stop ART without viral rebound. Both approaches may harness HIV-1-specific CD8+ T cells to achieve the reduction or elimination of the HIV-1 reservoir. However, variations (or mutations) in viral particles that exist in the HIV-1 reservoir may limit the capacity of these T cells to recognize and clear virus-infected cells, meaning the cells can escape detection and go on to cause viral rebound. “In our study, we wanted to determine the frequency and patterns of T-cell escape mutations in the HIV-1 reservoir of people who are on ART,” Warren says.

To do this, the UNC team measured HIV-1-specific T-cell responses and isolated reservoir virus in 25 people living with HIV who are on ART. Of these participants, four started on ART during acute HIV-1 infection, which means virus levels were controlled early, while the other 21 started on ART during chronic HIV-1 infection, which means considerable virus mutation occurred before virus levels were controlled.

In the HIV-1 proteome (the entire set of proteins expressed by the virus) for each participant, the researchers identified T-cell epitopes (regions of proteins that trigger an immune response). They sequenced HIV-1 ‘outgrowth’ viruses from resting CD4+ T cells and tested mutations in T-cell epitopes for their effect on the size of the T-cell response. These strategies revealed that the majority (68%) of T-cell epitopes did not harbor any detectable escape mutations, meaning circulating T cells could recognize the epitopes.

“Our findings show that the majority of HIV-1-specific T cells in people on ART can detect HIV viruses that have the capacity to rebound following treatment interruption,” Goonetilleke said. “This suggests that T cells likely help to control viral rebound and could be leveraged in future treatment strategies against HIV.”

Other authors Shuntai Zhou, Yinyan Xu, Matthew Moeser, Olivia Council, Jennifer Kirchherr, Julia M Sung, Adaora A Adimora, Sarah Joseph, JoAnn D Kuruc, Cynthia L Gay, David M Margolis, Nancie Archin, Zabrina L Brumme, and Ronald Swanstrom, from UNC-Chapel Hill, the HIV Cure Center, and the UNC Center for AIDS Research, and Nadio Roan from UC-San Francisco, and Daniel MacMillan from the British Columbia Centre for Excellence in HIV/AIDS.

Media contacts

Emily Packer, Media Relations Manager, eLife

Mark Derewicz, UNC School of Medicine