TY - JOUR
T1 - Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation
AU - El-Far, Mohamed
AU - Ancuta, Petronela
AU - Routy, Jean Pierre
AU - Zhang, Yuwei
AU - Bakeman, Wendy
AU - Bordi, Rebeka
AU - DaFonseca, Sandrina
AU - Said, Elias A.
AU - Gosselin, Annie
AU - Tep, Tévy Suzy
AU - Eichbaum, Quentin
AU - van Grevenynghe, Julien
AU - Schwartz, Olivier
AU - Freeman, Gordon J.
AU - Haddad, Elias K.
AU - Chomont, Nicolas
AU - Sékaly, Rafick Pierre
N1 - Publisher Copyright:
© 2015 The Author.
PY - 2015
Y1 - 2015
N2 - 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.
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.
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U2 - 10.1099/vir.0.000065
DO - 10.1099/vir.0.000065
M3 - Article
AN - SCOPUS:84937622269
SN - 0022-1317
VL - 96
SP - 1463
EP - 1477
JO - Journal of General Virology
JF - Journal of General Virology
ER -