Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection
Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection
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DOI：
10.4049/jimmunol.180.8.5439
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发表时间：
2008-04-15
影响因子：
4.4
通讯作者：
Franchini, Genoveffa
中科院分区：
文献类型：
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作者：
Cecchinato, Valentina;Tryniszewska, Elzbieta;Franchini, Genoveffa
在HIV感染者和SIV感染的非人灵长类动物模型中进行的相关研究已经推断出慢性免疫激活在AIDS进展中的重要性。使用SIVmac 251猕猴模型，我们通过抑制CTLA-4直接解决免疫活化的影响，CTLA-4是一种在活化T细胞和调节性T细胞亚群上表达的免疫调节分子。我们发现，CTLA-4阻断显著增加了原发性SIVmac 251感染中的T细胞活化和病毒复制，特别是在粘膜部位，并增加了IDO表达和活性。因此，用抗CTLA-4 Ab长期治疗慢性感染SIVmac 251的猕猴降低了对抗逆转录病毒疗法的应答性，并消除了治疗性T细胞疫苗降低病毒设定点的能力。这些数据提供了免疫激活驱动病毒复制的第一个直接证据，并建议谨慎使用体内HIV感染的治疗方法，增加CD 4（+）T细胞增殖。
The importance of chronic immune activation in progression to AIDS has been inferred by correlative studies in HIV-infected individuals and in nonhuman primate models of SIV infection. Using the SIVmac251 macaque model, we directly address the impact of immune activation by inhibiting CTLA-4, an immunoregulatory molecule expressed on activated T cells and a subset of regulatory T cells. We found that CTLA-4 blockade significantly increased T cell activation and viral replication in primary SIVmac251 infection, particularly at mucosal sites, and increased IDO expression and activity. Accordingly, protracted treatment with anti-CTLA-4 Ab of macaques chronically infected with SIVmac251 decreased responsiveness to antiretroviral therapy and abrogated the ability of therapeutic T cell vaccines to decrease viral set point. These data provide the first direct evidence that immune activation drives viral replication, and suggest caution in the use of therapeutic approaches for HIV infection in vivo that increase CD4(+) T cell proliferation.