Association between HIV-1 Nef-mediated MHC-I downregulation and the maintenance of the replication-competent latent viral reservoir in individuals with virally suppressed HIV-1 in Uganda: an exploratory cohort study.

• Tác giả: Aggrey Anok, Owen R Baker, Erin E Brown, Paul Buule, Adam A Capoferri, Gregory A Dekaban, Jimmy D Dikeakos, Cassandra R Edgar, Roux-Cil Ferreira, Corby Fink, Ronald M Galiwango, Jada Hackman, Samiri Jamiru, Charles Kirby, Taddeo Kityamuweesi, Ethan Klock, Briana Lynch, Jernelle C Miller, Mitchell J Mumby, Art F Y Poon, Jessica L Prodger, Thomas C Quinn, Andrew D Redd, Steven J Reynolds, Sharada Saraf, Aaron A R Tobian, Stephen Tomusange, Steven M Trothen, Xianming Zhu
• Ngôn ngữ: eng
• Thông tin xuất bản: England : The Lancet. Microbe , 2025
• Bộ sưu tập: NCBI
• ID: 713677

Tóm tắt

 BACKGROUND: The persistence of a replication-competent latent viral reservoir (RC-LVR) during antiretroviral therapy (ART) is a barrier to the development of a cure for HIV-1, but the role of viral genes in influencing RC-LVR size is unclear. We aimed to assess whether the magnitude by which the HIV-1 accessory protein Nef evades the adaptive immune response by downregulating MHC-I or CD4, or both, from the surface of infected cells is associated with the rate at which the RC-LVR in people with HIV-1 changes during long-term ART (>
 1 year). METHODS: We conducted an exploratory cohort study in which nef genes were sequenced from outgrowth viruses derived from the quantitative viral outgrowth assay (QVOA) for a group of people with ART-suppressed HIV-1 in Uganda between 2015 and 2020. Study participants were selected from the Rakai Health Sciences Program (RHSP) LVR cohort, a cohort of 90 adults (aged ≥18 years) who were HIV-1 positive, receiving ART, and had maintained viral suppression for at least 1 year at the time of study enrolment. For this study, participants were required to have available p24 FINDINGS: 14 (15%) of 90 participants from the RHSP cohort met the inclusion criteria and were enrolled in this study. 49 nef sequences were isolated from these participants. We observed variability in participant-derived Nef-mediated cell surface MHC-I downregulation (median 114·88% [IQR 104·93-121·51] of the downregulation capacity of NL4-3 Nef) and CD4 downregulation (94·50% [84·05-100·16] of NL4-3 Nef). The estimated rate of change of the RC-LVR was positive for four participants. For one donor, the rate of change was significantly positive (7·4 × 10 INTERPRETATION: Nef-mediated MHC-I downregulation might contribute to HIV-1 persistence during long-term ART. Strategies to inhibit Nef-mediated MHC-I downregulation could represent a viable therapeutic avenue to reduce the size of the latent reservoir in vivo, improving treatment outcomes in people with HIV-1. FUNDING: Canadian Institutes of Health Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the REACH Martin Delaney Collaboratory.