New compound reverses HIV latency in macaque models

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Published recently in Nature, a research collaboration between University of North Carolina at Chapel Hill (UNC-Chapel Hill; NC, USA), Emory University (GA, USA) and Qura Therapeutics (NC, USA), has enabled the discovery of a compound named ‘AZD5582’, which when tested in mice and macaques, exposed HIV/SIV latently infected cells to the body’s natural immune system.

AZD5582, a mimetic of the protein SMAC, results in the persistent activation of the non-canonical NK-kB pathways in CD4+ T cells. Unlike previous studies that triggered the canonical NK-kB pathway, the non-canonical route results in fewer downstream effects, thus limiting its toxicity.

In vivo, AZD5582 was given to ART-suppressed murine models containing human CD4+ T cells. The team demonstrated that AZD5582 increased viral RNA more than 20-fold, with RNA also being detected in lymphoid organs, lungs and brain.

The researchers also demonstrated the same response in ART-suppressed, SIV-infected macaques when AZD5582 was given in multiple weekly doses. Little toxicity was reported in both studies.

“Previously, no one had successfully tested a latency reversal molecule in humans or in an animal model with human cells demonstrating systemic HIV induction in peripheral blood, in resting CD4+ T cells from multiple tissues and then replicated this success in a completely different species infected with a different virus,” stated author Victor Garcia (UNC-Chapel Hill).

“AZD5582 was remarkable in its ability to reactivate latent SIV from resting CD4+ T cells, and to induce continued virus production in the blood when monkeys were still receiving daily antiretroviral therapy” commented co-author Ann Chahroudi (Emory University).

In a second collaborative paper, also published in the same issue of Nature, the researchers injected an antibody into ART-suppressed non-human primates, which depleted their CD8+ cells. After being given an altered version of the cytokine IL-15, which normally plays a pivotal role in both the innate and adaptive immune response, the researchers noted viral RNA in the blood and tissues therefore, suggesting a second route for HIV reactivation. These results were also confirmed in the previous murine models on HIV infection.

Qura Therapeutics, a partnership between UNC and ViiV Healthcare (NC, USA), has suggested that they will be working to create a compound similar to AZD5582, in the hope that 2021 may see the first safety studies in humans.

“This is an exciting scientific achievement and we hope this will be an important step toward one day eradicating the virus in people living with HIV” concluded Chahroudi.

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Source: www.eurekalert.org/emb_releases/2020-01/uonc-rrh012120.php

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