Role of Nef-mediated TCR-CD3 downmodulation in the pathogenesis of AIDS

Nef 介导的 TCR-CD3 下调在 AIDS 发病机制中的作用

• 批准号: 59205606
• 负责人: Professor Dr. Frank Kirchhoff
• 金额: --
• 依托单位: Institut für Molekulare Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/59205606?language=en
• 关键词: Role; Nef; mediated; TCR; CD3

Recently, we have shown that the inability of Nef to downmodulate TCR-CD3 may explain why high-level immune activation and AIDS represent a hallmark of HIV-1 infection but is absent from asymptomatic natural SIV infections. We also found that nef alleles from naturally SIVsmm-infected sooty mangabeys preserving their CD4+ T-cell counts exhibit significantly higher activity in TCR-CD3 downmodulation than those derived from the minor percentage of animals with low CD4+ T-cell numbers. These data suggest that the ability of Nef to downmodulate TCR-CD3 may allow the natural simian hosts of SIV to remain immunocompetent and healthy despite high levels of viral replication. However, direct evidence fora protective role of TCR-CD3 downmodulation in vivo is missing. Therefore, we want to compare the pathogenicity and immunological properties of SIVagm variants differing specifically in the ability of Nef to modulate TCR-CD3 in infected African Green Monkeys. The results of this study will clarify whether inhibition of T-cell activation by CDS downregulation protects against AIDS and help to assess whether treatments preventing hyperactivation of the immune response in infected humans - mimicking the tight balance maintained in the other primates - may offer new prospects for antiretroviral therapy.

最近，我们发现Nef不能下调TCR-CD3，这可能解释了为什么高水平的免疫激活和艾滋病是HIV-1感染的标志，而在无症状的自然SIV感染中则不存在。我们还发现，来自自然感染SIVsmm的煤鸟的nef等位基因，保持它们的CD4+T细胞数量，在TCR-CD3下调中的活性明显高于那些来自低CD4+T细胞数量的小比例动物的NEF等位基因。这些数据表明，Nef下调TCR-CD3的能力可能允许SIV的自然宿主保持免疫活性和健康，尽管病毒复制水平很高。然而，缺乏体内TCR-CD3下调具有保护作用的直接证据。因此，我们想要比较SIVagm变异体的致病性和免疫学特性，特别是在Nef调节感染的非洲绿猴TCR-CD3的能力方面。这项研究的结果将澄清CDS下调对T细胞激活的抑制是否可以预防艾滋病，并有助于评估防止感染人类免疫反应过度激活的治疗方法-模仿其他灵长类动物保持的紧密平衡-是否可能为抗逆转录病毒治疗提供新的前景。