HIV-1 mutants that escape the cytotoxic T-lymphocytes are defective in viral DNA integration. Issue 2 (20th May 2022)

• Record Type: Journal Article
• Authors: Balasubramaniam, Muthukumar; Davids, Benem-Orom; Bryer, Alex; Xu, Chaoyi; Thapa, Santosh; Shi, Jiong; Aiken, Christopher; Pandhare, Jui; Perilla, Juan R; Dash, Chandravanu
• Editors: Brenner, David
• Is Part Of: PNAS nexus. Volume 1:Issue 2(2022)
• Publication Date: 2022-05-20
• Subjects: human immunodeficiency virus (HIV) -- cytotoxic T lymphocytes (CTL) -- capsid -- integration -- reverse transcription; Science -- Periodicals; 505
• DOI: 10.1093/pnasnexus/pgac064
• Languages: English
• ISSNs: 2752-6542

Abstract

Abstract: HIV-1 replication is durably controlled without antiretroviral therapy (ART) in certain infected individuals called elite controllers (ECs). These individuals express specific human leukocyte antigens (HLA) that tag HIV-infected cells for elimination by presenting viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In HIV-infected individuals expressing HLA-B27, CTLs primarily target the viral capsid protein (CA)-derived KK10 epitope. While selection of CA mutation R264K helps HIV-1 escape this potent CTL response, the accompanying fitness cost severely diminishes virus infectivity. Interestingly, selection of a compensatory CA mutation S173A restores HIV-1 replication. However, the molecular mechanism(s) underlying HIV-1 escape from this ART-free virus control by CTLs is not fully understood. Here, we report that the R264K mutation-associated infectivity defect arises primarily from impaired HIV-1 DNA integration, which is restored by the S173A mutation. Unexpectedly, the integration defect of the R264K variant was also restored upon depletion of the host cyclophilin A. These findings reveal a nuclear crosstalk between CA and HIV-1 integration as well as identify a previously unknown role of cyclophilin A in viral DNA integration. Finally, our study identifies a novel immune escape mechanism of an HIV-1 variant escaping a CA-directed CTL response.