New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts, United States of America.
PLoS Biol. 2010 Aug 24;8(8):e1000462. doi: 10.1371/journal.pbio.1000462.
Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and SIVstm in stump-tailed macaques. Cellular assays and phylogenetic comparisons indirectly support a role for TRIM5alpha, the product of the TRIM5 gene, in suppressing interspecies transmission and emergence of retroviruses in nature. Here, we investigate the in vivo role of TRIM5 directly, focusing on transmission of primate immunodeficiency viruses between outbred primate hosts. Specifically, we retrospectively analyzed experimental cross-species transmission of SIVsm in two cohorts of rhesus macaques and found a significant effect of TRIM5 genotype on viral replication levels. The effect was especially pronounced in a cohort of animals infected with SIVsmE543-3, where TRIM5 genotype correlated with approximately 100-fold to 1,000-fold differences in viral replication levels. Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection. In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239. Adaptations appeared in the viral capsid in animals with restrictive TRIM5 genotypes, and similar adaptations coincide with emergence of SIVmac in captive macaques in the 1970s. Thus, host TRIM5 can suppress viral replication in vivo, exerting selective pressure during the initial stages of cross-species transmission.
食蟹猴的猴免疫缺陷病毒（SIVsm）是多种成功的跨物种传播的来源，它在人类中产生了 HIV-2，在恒河猴中产生了 SIVmac，在短尾猴中产生了 SIVstm。细胞测定和系统发育比较间接支持 TRIM5alpha（TRIM5 基因的产物）在抑制种间传播和自然中逆转录病毒的出现中发挥作用。在这里，我们直接研究 TRIM5 的体内作用，重点关注不同种属灵长类动物之间的灵长类免疫缺陷病毒的传播。具体来说，我们回顾性地分析了恒河猴中两个队列中 SIVsm 的实验性跨种传播，发现 TRIM5 基因型对病毒复制水平有显著影响。这种影响在感染 SIVsmE543-3 的动物队列中尤为明显，TRIM5 基因型与病毒复制水平的差异约为 100 倍至 1000 倍。令人惊讶的是，即使在携带限制型 TRIM5 基因型的个体中也发生了传播，导致复制减弱，而不是感染完全受阻。在细胞培养测定中，与体内病毒抑制相关的相同 TRIM5 等位基因阻断了两种 SIVsm 株的感染性，但不能阻断适应于猴的 SIVmac239 株的感染性。在具有限制型 TRIM5 基因型的动物中，病毒衣壳发生了适应性改变，类似的适应性改变与 20 世纪 70 年代圈养恒河猴中 SIVmac 的出现相吻合。因此，宿主 TRIM5 可以在体内抑制病毒复制，在跨种传播的初始阶段施加选择压力。
