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HIV-1 Nef mediates immune evasion and viral pathogenesis in part through downregulation of cell surface cluster of differentiation 4 (CD4) and major histocompatibility complex class I (MHC-I) on infected cells. While 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 persistence of viral variants during long-term antiretroviral therapy (ART). Phylogenetically distinct nef genes (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=16). These nef 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 (QVOA) 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 (p=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's role in the survival of individual viral variants over time.

Objectives: As topical pre-exposure prophylaxis (PrEP) has been shown to cause immune modulation in rectal or cervical tissue, our aim was to examine the impact of oral PrEP on lymphoid and myeloid changes in the foreskin in response to dosing and timing of drug administration., Design: HIV-negative male individuals ( n  = 144) were recruited in South Africa and Uganda into an open-label randomized controlled trial in a 1 : 1 : 1 : 1 : 1 : 1 : 1 : 1 : 1 ratio to control arm (with no PrEP) or one of eight arms receiving emtricitabine-tenofovir disoproxil fumarate (F/TDF) or emtricitabine-tenofovir alafenamide (F/TAF) at one of two different doses, 5 or 21 h before undergoing voluntary medical male circumcision (VMMC)., Methods: After dorsal-slit circumcision, foreskin tissue sections were embedded into Optimal Cutting Temperature media and analysed, blinded to trial allocation, to determine numbers of CD4 + CCR5 + , CD1a + cells and claudin-1 expression. Cell densities were correlated with tissue-bound drug metabolites and p24 production after ex-vivo foreskin challenge with HIV-1 bal ., Results: There was no significant difference in CD4 + CCR5 + or CD1a + cell numbers in foreskins between treatment arms compared with the control arm. Claudin-1 expression was 34% higher ( P  = 0.003) in foreskin tissue from participants receiving PrEP relative to controls, but was no longer statistically significant after controlling for multiple comparisons. There was neither correlation of CD4 + CCR5 + , CD1a + cell numbers, or claudin-1 expression with tissue-bound drug metabolites, nor with p24 production after ex-vivo viral challenge., Conclusion: Oral doses and timing of on-demand PrEP and in-situ drug metabolite levels in tissue have no effect on numbers or anatomical location of lymphoid or myeloid HIV target cells in foreskin tissue., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We compared outer and inner foreskin tissue from adolescent males undergoing medical male circumcision to better understand signals that increase HIV target cell availability in the foreskin. We measured chemokine gene expression and the impact of sexually transmitted infections (STIs) on the density and location of T and Langerhans cells. Chemokine C-C ligand 27 (CCL27) was expressed 6.94-fold higher in the inner foreskin when compared with the outer foreskin. We show that the density of CD4 + CCR5 + cells/mm 2 was higher in the epithelium of the inner foreskin, regardless of STI status, in parallel with higher CCL27 gene expression. In the presence of STIs, there were higher numbers of CD4 + CCR5 + cells/mm 2 cells in the sub-stratum of the outer and inner foreskin with concurrently higher number of CD207 + Langerhans cells (LC) in both tissues, with the latter cells being closer to the keratin surface of the outer FS in the presence of an STI. When we tested the ability of exogenous CCL27 to induce T-cell migration in foreskin tissue, CD4 + T cells were able to relocate to the inner foreskin epithelium in response. We provide novel insight into the impact CCL27 and STIs on immune and HIV-1 target cell changes in the foreskin.