Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation

Mohamed El-Far, Petronela Ancuta, Jean Pierre Routy, Yuwei Zhang, Wendy Bakeman, Rebeka Bordi, Sandrina DaFonseca, Elias A. Said, Annie Gosselin, Tévy Suzy Tep, Quentin Eichbaum, Julien van Grevenynghe, Olivier Schwartz, Gordon J. Freeman, Elias K. Haddad, Nicolas Chomont*, Rafick Pierre Sékaly

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1463-1477
Number of pages15
JournalJournal of General Virology
Issue numberPt 6
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Virology


Dive into the research topics of 'Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation'. Together they form a unique fingerprint.

Cite this