Schindler Michael, Münch Jan, Kutsch Olaf, Li Hui, Santiago Mario L, Bibollet-Ruche Frederic, Müller-Trutwin Michaela C, Novembre Francis J, Peeters Martine, Courgnaud Valerie, Bailes Elizabeth, Roques Pierre, Sodora Donald L, Silvestri Guido, Sharp Paul M, Hahn Beatrice H, Kirchhoff Frank
Department of Virology, University of Ulm, 89081 Ulm, Germany.
Cell. 2006 Jun 16;125(6):1055-67. doi: 10.1016/j.cell.2006.04.033.
High-level immune activation and T cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic SIV infections in natural primate hosts. The mechanisms causing these varying levels of immune activation are not understood. Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation. In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death. Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system. This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans.
高水平免疫激活和T细胞凋亡是HIV-1感染的一个标志，而在天然灵长类宿主的非致病性SIV感染中并不存在。导致这些不同程度免疫激活的机制尚不清楚。在此，我们报告，包括HIV-2在内的绝大多数灵长类慢病毒的nef等位基因可下调受感染T细胞上的TCR-CD3，从而阻断其对激活的反应性。相比之下，HIV-1和一部分密切相关的SIV的nef等位基因无法下调TCR-CD3，也无法抑制细胞死亡。因此，Nef介导的对T细胞激活的抑制是灵长类慢病毒的一个基本特性，这一特性可能是在完整宿主免疫系统的背景下进化而来以维持病毒持续存在。在产生HIV-1的病毒谱系进化过程中，这一功能丧失了，这可能使HIV-1的猿类前体在人类中具有更大的致病性。
