Characterising the effect of the capsid inhibitor Lenacapavir on immune clearance of HIV-1-infected cells

Daniƫl Roovers (Liverpool School of Tropical Medicine, UK)

14:54 - 15:06 Tuesday 14 April Afternoon

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Abstract

The novel, long acting HIV-1 capsid inhibitor Lenacapavir reduces intracellular capsid levels. While the mechanism for this effect remains unknown, Lenacapavir has been approved for treatment and prevention of HIV-1 infection, raising questions of how Lenacapavir affects immunological visibility and immune clearance of HIV-1-infected cells in people living with HIV-1. The aim of this study is to investigate the quantitative and qualitative impact of Lenacapavir on the presentation of HIV-1 gag peptides by MHC-I, with potential implications on CD8+ T-cell responses directed against HIV-1-infected cells. Upon latency reversal by treatment with the HDAC inhibitor Panobinostat, surface Env levels were maintained in the presence of Lenacapavir, as expected, suggesting that Lenacapavir is not likely to adversely affect susceptibility to antibody-mediated cytotoxicity. To study the consequence of Lenacapavir treatment on gag peptide presentation, cellular and HIV-1-derived peptides presented on the cell surface by MHC-I were isolated and analysed using LC-MS. Several HIV-1-derived peptides, some of them in quantifiable amounts, were identified in Panobinostat-treated, HIV-1-infected cell lines, as opposed to in mock-treated HIV-1-infected, and HIV-1-negative cell lines. The full dataset is currently being analysed and will be presented. Additionally, metabolic labelling by click chemistry is currently being established to quantify a potentially altered half-life of capsid in the presence of Lenacapavir. A better understanding of how Lenacapavir treatment affects various pathways for immune clearance of HIV-1-infected cells is crucial for the development of optimised strategies that aim at achieving a functional cure for HIV-1 under ART.

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