Enhanced Anti-HIV Functional Activity Associated with Gag-Specific CD8 T-Cell Responses

被引:79
作者
Julg, B. [1 ,2 ,3 ]
Williams, K. L. [1 ,2 ,3 ]
Reddy, S. [1 ,2 ]
Bishop, K. [1 ,2 ]
Qi, Y. [4 ]
Carrington, M. [3 ,4 ]
Goulder, P. J. [1 ,2 ,3 ,5 ]
Ndung'u, T. [1 ,2 ,3 ]
Walker, B. D. [1 ,2 ,3 ,6 ]
机构
[1] Univ KwaZulu Natal, HIV Pathogenesis Program, Doris Duke Med Res Inst, Durban, South Africa
[2] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Durban, South Africa
[3] MIT & Harvard, Ragon Inst MGH, Boston, MA USA
[4] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA
[5] Univ Oxford, Dept Pediat, Oxford, England
[6] Howard Hughes Med Inst, Chevy Chase, MD USA
基金
英国惠康基金;
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL LOAD; TYPE-1; REPLICATION; IMMUNE CONTROL; EX-VIVO; LYMPHOCYTES; INFECTION; HLA; EXPRESSION; PROTEINS;
D O I
10.1128/JVI.02031-09
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 (>= 6; n = 13) or narrow (<= 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.
引用
收藏
页码:5540 / 5549
页数:10
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