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

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: Sup-T1 cells via flow cytometry. The size and rate of change of the RC-LVR in participants was estimated using previous QVOA results and a Bayesian model. We then assessed whether a correlation existed between the extent to which the Nef proteins downregulated cell surface MHC-I and CD4 and the calculated RC-LVR rate of change during the study period. FINDINGS: ]). A significant relationship between Nef-mediated MHC-I downregulation and the RC-LVR rate of change during the 5-year study period (r=0·6088 [95% CI 0·2366 to 0·9810]; p=0·023) was found, in which less efficient MHC-I downregulation correlated with faster RC-LVR decay during long-term ART. By contrast, Nef-mediated CD4 downregulation was not associated with RC-LVR rate of change during the 5-year study period (-0·1604 [-0·7311 to 0·4102]; p=0·58). 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.