HIV Pathogenesis Program, Doris Duke Medical Research Institute and KwaZulu Natal Research Institute for TB and HIV, University of KwaZulu Natal, Durban, South Africa.
J Virol. 2010 Jun;84(11):5540-9. doi: 10.1128/JVI.02031-09. Epub 2010 Mar 24.
Effective HIV-specific T-cell immunity requires the ability to inhibit virus replication in the infected host, but the functional characteristics of cells able to mediate this effect are not well defined. Since Gag-specific CD8 T cells have repeatedly been associated with lower viremia, we examined the influence of Gag specificity on the ability of unstimulated CD8 T cells from chronically infected persons to inhibit virus replication in autologous CD4 T cells. Persons with broad (>or=6; n = 13) or narrow (<or=1; n = 13) Gag-specific responses, as assessed by gamma interferon enzyme-linked immunospot assay, were selected from 288 highly active antiretroviral therapy (HAART)-naive HIV-1 clade C-infected South Africans, matching groups for total magnitude of HIV-specific CD8 T-cell responses and CD4 T-cell counts. CD8 T cells from high Gag responders suppressed in vitro replication of a heterologous HIV strain in autologous CD4 cells more potently than did those from low Gag responders (P < 0.003) and were associated with lower viral loads in vivo (P < 0.002). As previously shown in subjects with low viremia, CD8 T cells from high Gag responders exhibited a more polyfunctional cytokine profile and a stronger ability to proliferate in response to HIV stimulation than did low Gag responders, which mainly exhibited monofunctional CD8 T-cell responses. Furthermore, increased polyfunctionality was significantly correlated with greater inhibition of viral replication in vitro. These data indicate that enhanced suppression of HIV replication is associated with broader targeting of Gag. We conclude that it is not the overall magnitude but rather the breadth, magnitude, and functional capacity of CD8 T-cell responses to certain conserved proteins, like Gag, which predict effective antiviral HIV-specific CD8 T-cell function.
有效的 HIV 特异性 T 细胞免疫需要能够抑制感染宿主中的病毒复制，但介导这种效应的细胞的功能特征尚未得到很好的定义。由于 Gag 特异性 CD8 T 细胞与较低的病毒血症反复相关，我们研究了 Gag 特异性对慢性感染个体未刺激的 CD8 T 细胞抑制自身 CD4 T 细胞中病毒复制能力的影响。通过γ干扰素酶联免疫斑点分析评估，从 288 名接受高效抗逆转录病毒治疗 (HAART) 治疗的 HIV-1 克拉德 C 感染南非人中选择具有广泛 (>或=6；n = 13) 或狭窄 (<或=1；n = 13) Gag 特异性反应的个体，与 HIV-1 特异性 CD8 T 细胞反应的总幅度和 CD4 T 细胞计数相匹配。高 Gag 应答者的 CD8 T 细胞比低 Gag 应答者更有效地抑制异源 HIV 株在自身 CD4 细胞中的复制（P < 0.003），并且与体内更低的病毒载量相关（P < 0.002）。如先前在病毒载量较低的患者中所显示的，高 Gag 应答者的 CD8 T 细胞表现出更多功能的细胞因子谱，并且在受到 HIV 刺激时比低 Gag 应答者更强烈地增殖，低 Gag 应答者主要表现出单功能 CD8 T 细胞应答。此外，增加的多功能性与体外病毒复制的更大抑制显著相关。这些数据表明，增强的 HIV 复制抑制与 Gag 的更广泛靶向相关。我们得出结论，不是总体幅度，而是针对某些保守蛋白（如 Gag）的 CD8 T 细胞反应的广度、幅度和功能能力，预测有效的抗病毒 HIV 特异性 CD8 T 细胞功能。
