Thippeshappa Rajesh, Kimata Jason T, Kaushal Deepak
Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States.
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States.
Front Microbiol. 2020 May 13;11:882. doi: 10.3389/fmicb.2020.00882. eCollection 2020.
The human-specific tropism of Human Immunodeficiency Virus Type 1 (HIV-1) has complicated the development of a macaque model of HIV-1 infection/AIDS that is suitable for preclinical evaluation of vaccines and novel treatment strategies. Several innate retroviral restriction factors, such as APOBEC3 family of proteins, TRIM5α, BST2, and SAMHD1, that prevent HIV-1 replication have been identified in macaque cells. Accessory proteins expressed by Simian Immunodeficiency virus (SIV) such as viral infectivity factor (Vif), viral protein X (Vpx), viral protein R (Vpr), and negative factor (Nef) have been shown to play key roles in overcoming these restriction factors in macaque cells. Thus, substituting HIV-1 accessory genes with those from SIV may enable HIV-1 replication in macaques. We and others have constructed macaque-tropic HIV-1 derivatives [also called simian-tropic HIV-1 (stHIV-1) or Human-Simian Immunodeficiency Virus (HSIV)] carrying SIV to overcome APOBEC3 family proteins. Additional modifications to HIV-1 in some of the macaque-tropic HIV-1 have also been done to overcome TRIM5α restriction in rhesus and cynomolgus macaques. Although these viruses replicate persistently in macaque species, they do not result in CD4 depletion. Thus, these studies suggest that additional blocks to HIV-1 replication exist in macaques that prevent high-level viral replication. Furthermore, serial animal-to-animal passaging of macaque-tropic HIV-1 has not resulted in pathogenic variants that cause AIDS in immunocompetent macaques. In this review, we discuss recent developments made toward developing macaque model of HIV-1 infection.
1型人类免疫缺陷病毒（HIV-1）具有人类特异性嗜性，这使得适合对疫苗和新型治疗策略进行临床前评估的HIV-1感染/艾滋病猕猴模型的开发变得复杂。在猕猴细胞中已鉴定出几种先天性逆转录病毒限制因子，如载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3）蛋白家族、三聚体基序蛋白5α（TRIM5α）、骨髓基质细胞抗原2（BST2）和SAM域和HD结构域蛋白1（SAMHD1），它们可阻止HIV-1复制。猴免疫缺陷病毒（SIV）表达的辅助蛋白，如病毒感染性因子（Vif）、病毒蛋白X（Vpx）、病毒蛋白R（Vpr）和负因子（Nef），已被证明在克服猕猴细胞中的这些限制因子方面发挥关键作用。因此，用来自SIV的辅助基因替代HIV-1辅助基因可能使HIV-1在猕猴中复制。我们和其他人构建了携带SIV的猕猴嗜性HIV-1衍生物[也称为猿猴嗜性HIV-1（stHIV-1）或人猿免疫缺陷病毒（HSIV）]，以克服APOBEC3家族蛋白。在一些猕猴嗜性HIV-1中，还对HIV-1进行了额外修饰，以克服恒河猴和食蟹猕猴中的TRIM5α限制。尽管这些病毒在猕猴物种中持续复制，但它们不会导致CD4耗竭。因此，这些研究表明，猕猴中存在阻止HIV-1高水平复制的其他障碍。此外，猕猴嗜性HIV-1在动物间的连续传代并未产生在免疫功能正常的猕猴中导致艾滋病的致病变体。在这篇综述中，我们讨论了在开发HIV-1感染猕猴模型方面取得的最新进展。
