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Nef promotes evasion of HIV-1 infected cells from the CTLA-4-mediated inhibition of T cell activation

El-Far, Mohamed; Ancuta, Petronela; Routy, Jean-Pierre; Zhang, Yuwei; Bakeman, Wendy; Bordi, Rebeka; DaFonseca, Sandrina; Said, Elias A; Gosselin, Annie; Tep, Tevy-Suzy; Eichbaum, Quentin; van Grevenynghe, Julien; Schwartz, Olivier; Freeman, Gordon J; Haddad, Elias K; Chomont, Nicolas; Sekaly, Rafick-Pierre (2015). Nef promotes evasion of HIV-1 infected cells from the CTLA-4-mediated inhibition of T cell activation Journal of General Virology , vol. 96 , nº Pt 6. p. 1463-77. DOI: 10.1099/vir.0.000065.

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Résumé

CTLA-4 is a negative regulator of TCR-mediated CD4+ T-cell activation and function. Up-regulation of CTLA-4 during 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 down-regulation 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 proviral 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+CD4negCD8neg (double negative, DN) cells, we further quantified HIV DNA in the CTLA-4+ and CTLA-4neg sub-populations of these cells. Our results showed that DN T-cells lacking CTLA-4 expression were enriched in HIV-DNA compared to DN CTLA-4+ cells. Together, these results suggest that HIV-1 preferential infection of CD4+CTLA-4+ T-cells in vivo is followed by Nef-mediated concomitant down-regulation 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.

Type de document:
Mots-clés libres: Animal ; Retroviruses
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 23 juin 2017 05:12
Dernière modification: 23 juin 2017 05:12
URI: http://espace.inrs.ca/id/eprint/3182

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