Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6060, USA.
J Clin Invest. 2012 May;122(5):1644-52. doi: 10.1172/JCI61429. Epub 2012 Apr 16.
SIVs infecting wild-living apes in west central Africa have crossed the species barrier to humans on at least four different occasions, one of which spawned the AIDS pandemic. Although the chimpanzee precursor of pandemic HIV-1 strains must have been able to infect humans, the capacity of SIVcpz strains to replicate in human lymphoid tissues (HLTs) is not known. Here, we show that SIVcpz strains from two chimpanzee subspecies are capable of replicating in human tonsillary explant cultures, albeit only at low titers. However, SIVcpz replication in HLT was significantly improved after introduction of a previously identified human-specific adaptation at position 30 in the viral Gag matrix protein. An Arg or Lys at this position significantly increased SIVcpz replication in HLT, while the same mutation reduced viral replication in chimpanzee-derived CD4(+) T cells. Thus, naturally occurring SIVcpz strains are capable of infecting HLTs, the major site of HIV-1 replication in vivo. However, efficient replication requires the acquisition of a host-specific adaptation in the viral matrix protein. These results identify Gag matrix as a major determinant of SIVcpz replication fitness in humans and suggest a critical role in the emergence of HIV/AIDS.
SIV 感染中非西部野生生活的猿类，至少有四次跨越物种屏障感染人类，其中一次引发了艾滋病大流行。虽然大流行 HIV-1 株的黑猩猩前体病毒一定能够感染人类，但 SIVcpz 株在人类淋巴组织（HLT）中的复制能力尚不清楚。在这里，我们表明两种黑猩猩亚种的 SIVcpz 株能够在人类扁桃体外植体培养物中复制，尽管只是在低滴度下。然而，在病毒 Gag 基质蛋白中引入先前鉴定的人类特异性适应性后，SIVcpz 在 HLT 中的复制显著改善。该位置的 Arg 或 Lys 显著增加了 SIVcpz 在 HLT 中的复制，而相同的突变降低了源自黑猩猩的 CD4(+) T 细胞中的病毒复制。因此，天然存在的 SIVcpz 株能够感染 HLT，这是 HIV-1 在体内复制的主要部位。然而，有效的复制需要在病毒基质蛋白中获得宿主特异性适应性。这些结果确定 Gag 基质蛋白是 SIVcpz 在人类中复制适应性的主要决定因素，并表明其在 HIV/AIDS 的出现中起着关键作用。
