Host Factor Genetics and Susceptibility to Retroviral Infection

摘要人类免疫缺陷病毒（HIV-1和HIV-2）是猴慢病毒从非人类旧世界灵长类动物向人类群体多次跨物种传播的结果。类似地，猴免疫缺陷病毒（SIVmac）的猕猴分离株最初是由非洲猴种偶然跨种传播到亚洲种引起的，用克隆SIVsm、SIVmac和HIV-2分离株实验性感染亚洲猕猴，导致广泛的结果。在非洲，超过24种灵长类动物也感染了猿猴免疫缺陷病毒。 与人类和亚洲猕猴不同，这些自然宿主的感染很少导致致病性结果。 宿主遗传变异表现在多个水平上，影响慢病毒在物种之间的移动，引起致病结果的物种水平差异，并（在物种或种群内）导致个体对感染易感性、疾病进展速率和发病严重程度的个体差异。在HIV/AIDS领域，已经鉴定了两个基因座APOBEC 3和TRIM 5，其编码慢病毒在人类和其他灵长类物种之间跨物种传播的内在屏障。我们发现，旧世界猴子的TRIM 5基因座，包括与艾滋病研究高度相关的多个物种，是高度多态的。恒河猴TRIM 5 <$的常见等位基因显示出不同的限制A 各种慢病毒。此外，我们在亚洲猕猴中发现了一种TRIM 5-CypA变体，它不限制HIV-1，但可以限制各种其他慢病毒。对宿主遗传变异的分类和了解有可能在若干领域影响艾滋病毒/艾滋病研究，包括确定新的治疗方案、改进动物模型和更清楚地解释临床试验结果。对影响慢病毒感染易感性的基因的研究也将阐明跨物种/人畜共患病传播易感性模式的控制过程以及致病性的物种特异性差异。 结果。本提案中描述的实验将利用天然存在的基因型和表型变异来建立内源性表达的进入后限制的生物学相关性，并确定遗传编码的限制因子影响灵长类慢病毒跨种属传播的潜力。

SUMMARY. The human immunodeficiency viruses (HIV-1 and HIV-2) are the result of multiple cross-species transmissions of simian lentiviruses into the human population from nonhuman, old world primates. Similarly, macaque isolates of simian immunodeficiency virus (SIVmac) arose initially by accidental cross-species transmission from an African monkey species into an Asian species, and experimental infection of Asian macaques with clonal SIVsm, SIVmac and HIV-2 isolates, results in a broad range of outcomes. In Africa, more than two-dozen primate species are also endemically infected with simian immunodeficiency viruses. Unlike humans and Asian macaques, infection in these natural hosts rarely results in pathogenic outcome. Host genetic variation manifests at multiple levels, influencing the movement of lentiviruses between species, giving rise to species-level differences in pathogenic outcome and (within species or populations) resulting in individual-to-individual variation in susceptibility to infection, rates of disease progression and severity of pathogenesis. In the HIV/AIDS field two loci, APOBEC3 and TRIM5, have been identified as encoding intrinsic barriers to cross-species transmission of lentiviruses between humans and other primate species. We discovered that the TRIM5 loci of old world monkeys, including multiple species of high relevance to AIDS research, are highly polymorphic. Common alleles of rhesus TRIM5¿ display differential ability to restrict a variety of lentiviruses. Moreover, we have discovered a TRIM5-CypA variant in Asian macaques that does not restrict HIV-1, but which can restrict a variety of other lentiviruses. Cataloguing and understanding host genetic variation has the potential to impact HIV/AIDS research in several areas, including identification of new therapeutic regimens, improved animal models and clearer interpretation of results from clinical trials. The study of genes that influence susceptibility to lentiviral infection will also illuminate the processes that govern patterns of susceptibility to cross-species/zoonotic transmission and species-specific differences in pathogenic outcome. The experiments described in this proposal will take advantage of naturally occurring genotypic and phenotypic variation to establish biological relevance of endogenously expressed post-entry restriction, and to ascertain the potential of genetically encoded restriction factors to impact cross-species transmission of primate lentiviruses.