HIV-1 mutants that escape the cytotoxic T-lymphocytes are defective in viral DNA integration
| Author(s) | Balasubramaniam, Muthukumar | |
| Author(s) | Davids, Benem-Orom | |
| Author(s) | Bryer, Alex | |
| Author(s) | Xu, Chaoyi | |
| Author(s) | Thapa, Santosh | |
| Author(s) | Shi, Jiong | |
| Author(s) | Aiken, Christopher | |
| Author(s) | Pandhare, Jui | |
| Author(s) | Perilla, Juan R. | |
| Author(s) | Dash, Chandravanu | |
| Date Accessioned | 2023-10-11T18:32:30Z | |
| Date Available | 2023-10-11T18:32:30Z | |
| Publication Date | 2022-05-20 | |
| Description | © The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences. | |
| 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. | |
| Sponsor | This work was supported by the National Institutes of Health grants R01 AI136740, R01 DA 042348, R56 AI122960, R24 DA036420, R25AI1647610, R01AI162694, and U54 MD007586 to C.D., and the support from the Research Centers in Minority Institutions (RCMI) grant U54MD007586 to J.P. This work is also supported in part by the Meharry Translational Research Center (MeTRC) grant U54MD007593 and Tennessee CFAR grant P30 AI110527 from the National Institutes of Health to C.D. | |
| Citation | Muthukumar 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/pgac064 | |
| ISSN | 2752-6542 | |
| URL | https://udspace.udel.edu/handle/19716/33534 | |
| Language | en_US | |
| Publisher | PNAS Nexus | |
| dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
| Keywords | human immunodeficiency virus (HIV) | |
| Keywords | cytotoxic T lymphocytes (CTL) | |
| Keywords | capsid | |
| Keywords | integration | |
| Keywords | reverse transcription | |
| Keywords | good health and well-being | |
| Title | HIV-1 mutants that escape the cytotoxic T-lymphocytes are defective in viral DNA integration | |
| Type | Article |
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