RT Journal Article SR Electronic(1) A1 El-Far, Mohamed A1 Ancuta, Petronela A1 Routy, Jean-Pierre A1 Zhang, Yuwei A1 Bakeman, Wendy A1 Bordi, Rebeka A1 DaFonseca, Sandrina A1 Said, Elias A. A1 Gosselin, Annie A1 Tep, Tévy-Suzy A1 Eichbaum, Quentin A1 van Grevenynghe, Julien A1 Schwartz, Olivier A1 Freeman, Gordon J. A1 Haddad, Elias K. A1 Chomont, Nicolas A1 Sékaly, Rafick-PierreYR 2015 T1 Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation JF Journal of General Virology, VO 96 IS 6 SP 1463 OP 1477 DO https://doi.org/10.1099/vir.0.000065 PB Microbiology Society, SN 1465-2099, AB CTLA-4 is a negative regulator of T-cell receptor-mediated CD4+ T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4+ T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4+ T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4+ T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these in vitro results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4+CTLA-4+ T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells in vivo. As transcriptionally active HIV-1 and Nef expression in vivo were previously shown to take place mainly in the CD3+CD4–CD8– [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4+ and CTLA-4– subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4+ cells. Together, these results suggested that HIV-1 preferential infection of CD4+CTLA-4+ T cells in vivo was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA-4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis., UL https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.000065