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While the Nef function of circulating viral populations found early in infection has been associated with reservoir size in early-treated cohorts, there is limited research on how its activity impacts reservoir size in people initiating treatment during chronic infection. In addition, there is little research on its role in the persistence of viral variants during long-term antiretroviral therapy (ART). Phylogenetically distinct\n                      <jats:italic toggle=\"yes\">nef<\/jats:italic>\n                      genes (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 82) with varying estimated times of reservoir entry were selected from viral outgrowth variants stimulated from the reservoir of South African women living with HIV who initiated ART during chronic infection (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 16). These\n                      <jats:italic toggle=\"yes\">nef<\/jats:italic>\n                      genes were synthesized and used in a pseudovirus infection assay that measures CD4 and MHC-I downregulation via flow cytometry. Downregulation measures were compared to the size of the replication-competent viral reservoir (RC-VR), estimated by quantitative viral outgrowth assay at 5 years after treatment initiation, as well as proviral survival time. Maximum Nef-mediated MHC-I downregulation was significantly associated with RC-VR size (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.034), but this association was not observed for CD4 downregulation. Conversely, we did not find a consistent association between intraparticipant MHC-I or CD4 downregulation and the variant timing of entry into the reservoir. These data support a role for Nef-mediated MHC-I downregulation in determining RC-VR size, but more work is needed to determine Nef\u2019s role in the survival of individual viral variants over time.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Rational design of HIV cure interventions requires an understanding of the viral determinants of reservoir dynamics. For an equitable cure, it needs to be broadly applicable. While African women bear the greatest burden of HIV globally, most cure research has focused on men in the global North. Our study aims to elucidate viral determinants of HIV persistence in South African women on antiretroviral therapy. We hypothesized that the HIV protein Nef subverts immune clearance of infected cells by downregulating surface levels of two cellular proteins, CD4 and MHC-I. We compared this downregulation capacity with reservoir size and variant survival in the reservoir. We found a positive association between an individual\u2019s reservoir size and MHC-I downregulation, but there was little evidence for a survival benefit with stronger MHC-I reduction. These data support earlier work and suggest that Nef\u2019s interaction with MHC-I may be a target to restrict the latent reservoir in cure strategies.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00217-25","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T09:00:43Z","timestamp":1750755643000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["The role of Nef in the long-term persistence of the replication-competent HIV reservoir in South African women"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8098-9829","authenticated-orcid":true,"given":"Sherazaan D.","family":"Ismail","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Infectious Disease and Molecular Medicine, University of Cape 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