El-Far Mohamed, Ancuta Petronela, Routy Jean-Pierre, Zhang Yuwei, Bakeman Wendy, Bordi Rebeka, DaFonseca Sandrina, Said Elias A, Gosselin Annie, Tep Tévy-Suzy, Eichbaum Quentin, van Grevenynghe Julien, Schwartz Olivier, Freeman Gordon J, Haddad Elias K, Chomont Nicolas, Sékaly Rafick-Pierre
Department of Microbiology, Infectiology and Immunology, Université de Montréal, Québec, Canada.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
J Gen Virol. 2015 Jun;96(Pt 6):1463-1477. doi: 10.1099/vir.0.000065. Epub 2015 Jan 27.
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.
CTLA-4是T细胞受体介导的CD4(+) T细胞活化和功能的负调节因子。在1型人类免疫缺陷病毒（HIV-1）感染期间，活化T细胞尤其是HIV特异性CD4(+) T细胞上CTLA-4的上调与免疫功能障碍和疾病进展相关。由于HIV-1在活化的CD4(+) T细胞中感染和复制，我们研究了HIV-1调节CTLA-4表达以在这些细胞中建立有效病毒感染的机制。在此，我们证明活化的CD4(+) T细胞感染HIV-1后，Nef介导CTLA-4下调。这与T细胞活化阈值降低以及对CTLA-4触发的显著抗性相关。与这些体外结果一致，对未经治疗的HIV感染受试者的前病毒HIV DNA进行定量分析表明，记忆CD4(+)CTLA-4(+) T细胞优先被感染，从而确定CTLA-4为体内HIV感染细胞的生物标志物。由于先前已证明体内转录活性HIV-1和Nef表达主要发生在CD3(+)CD4(-)CD8(-) [双阴性（DN）]细胞中，我们进一步对这些细胞的CTLA-4(+)和CTLA-4(-)亚群中的HIV DNA进行了定量分析。我们的结果表明，与DN CTLA-4(+)细胞相比，缺乏CTLA-4表达的DN T细胞中HIV DNA更为富集。总之，这些结果表明，HIV-1在体内优先感染CD4(+)CTLA-4(+) T细胞，随后在转变为有效感染时，Nef介导CD4和CTLA-4同时下调。这也突出了HIV-1逃避关键负性免疫调节因子CTLA-4对细胞活化和病毒复制限制的倾向，因此有助于整体HIV-1发病机制。
