@article{mbs:/content/journal/jgv/10.1099/vir.0.000065, author = "El-Far, Mohamed and Ancuta, Petronela and Routy, Jean-Pierre and Zhang, Yuwei and Bakeman, Wendy and Bordi, Rebeka and DaFonseca, Sandrina and Said, Elias A. and Gosselin, Annie and Tep, Tévy-Suzy and Eichbaum, Quentin and van Grevenynghe, Julien and Schwartz, Olivier and Freeman, Gordon J. and Haddad, Elias K. and Chomont, Nicolas and Sékaly, Rafick-Pierre", title = "Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation", journal= "Journal of General Virology", year = "2015", volume = "96", number = "6", pages = "1463-1477", doi = "https://doi.org/10.1099/vir.0.000065", url = "https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.000065", publisher = "Microbiology Society", issn = "1465-2099", type = "Journal Article", abstract = "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.", }