Study offers new treatment strategies for HIV

According to a new study recently published in the eLife journal, immune cells that can detect residual HIV-infected cells in patients living with HIV (PLWH) and undergoing antiretroviral therapy (ART) continue to remain active for years.

HIV

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This discovery also indicates that most of these immune cells, known as CD8+ T cells, should have the ability to recognize the HIV-infected cells that fuel HIV-1 rebound after the treatment is interrupted. This understanding can help develop novel therapeutic approaches against HIV infection.

ART has changed HIV-1 from a deadly disease to a chronic condition in PLWH. But it should be taken by those who have the infection for the rest of their lives. This is because when treatment is interrupted, it usually enablesthe virus to rebound within weeks. This rebound ensues from cells harboring HIV-1 DNA that is incorporated into the human genome.

While more than 95% of proviral 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. The largest and most well-characterised HIV-1 reservoir resides in ‘resting’ CD4+ T cells, which circulate in the blood and are long-lived.”

Joanna Warren, Study Lead Author and Postdoctoral Investigator, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill

There are two approaches to enable HIV-1 patients to cease ART without viral rebound. Both methods may harness CD8+ T cells that are -specific to HIV-1 to achieve the elimination or reduction of the HIV-1 reservoir. But differences (or mutations) in viral particles existing in the HIV-1 reservoir may restrict the capacity of the CD8+ T cells to detect and eliminate the virus-infected cells, which means the cells can evade detection and continue 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.”

Joanna Warren, Study Lead Author and Postdoctoral Investigator, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill

To achieve this, the researchers quantified the responses of the HIV-1-specific T-cells and separated the reservoir virus in 25 PLWH who are on ART. Among these participants, four started on ART during acute HIV-1 infection, meaning that virus levels were regulated early, whereas the other 21 started on ART during chronic HIV-1 infection, meaning that significant virus mutation took place before virus levels were managed.

The team sequenced HIV-1 “outgrowth” viruses from resting CD4+ T cells and examined the mutations in T-cell epitopes to find out their impact on the size of the T-cell response. These approaches demonstrated that most (68%) of the T-cell epitopes did not harbor any perceptible escape mutations, which means they could be detected by circulating T cells.

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. This suggests that T cells likely help to control viral rebound and could be leveraged in future treatment strategies against HIV.”

Nilu Goonetilleke, Study Senior Author and Faculty Member, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill

Source:
Journal reference:

Warren, J. A., et al. (2020) The HIV-1 latent reservoir is largely sensitive to circulating T cells. eLife. doi.org/10.7554/eLife.57246.

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