Balasubramaniam, MuthukumarDavids, Benem-OromBryer, AlexXu, ChaoyiThapa, SantoshShi, JiongAiken, ChristopherPandhare, JuiPerilla, Juan R.Dash, Chandravanu2023-10-112023-10-112022-05-20Muthukumar Balasubramaniam, Benem-Orom Davids, Alex Bryer, Chaoyi Xu, Santosh Thapa, Jiong Shi, Christopher Aiken, Jui Pandhare, Juan R Perilla, Chandravanu Dash, HIV-1 mutants that escape the cytotoxic T-lymphocytes are defective in viral DNA integration, PNAS Nexus, Volume 1, Issue 2, May 2022, pgac064, https://doi.org/10.1093/pnasnexus/pgac0642752-6542https://udspace.udel.edu/handle/19716/33534© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.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.en-UShuman immunodeficiency virus (HIV)cytotoxic T lymphocytes (CTL)capsidintegrationreverse transcriptiongood health and well-beingArticle