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 TRIM5α, 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.
Citation: Kirmaier A, Wu F, Newman RM, Hall LR, Morgan JS, et al. (2010) TRIM5 Suppresses Cross-Species Transmission of a Primate Immunodeficiency Virus and Selects for Emergence of Resistant Variants in the New Species. PLoS Biol 8(8): e1000462. doi:10.1371/journal.pbio.1000462
Academic Editor: Michael Emerman, Fred Hutchinson Cancer Research Center, United States of America
Received: May 4, 2010; Accepted: July 14, 2010; Published: August 24, 2010
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: This work was supported by grants from the National Institutes of Health (NIH), including grants AI057039 and AI083118 (WEJ), NIH ARRA award AI077423 (WEJ), AI049809 and AI084810 (A Kaur), and by NIH/NCRR grant RR00168 (NEPRC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CA, capsid protein; CypA, cyclophilin-A; NTD, N-terminal domain; RF, restriction factor; SIVs, Simian immunodeficiency viruses; SIVmac, Simian immunodeficiency viruses of rhesus macaques; SIVsm, Simian immunodeficiency viruses of sooty mangabeys; SIVstm, Simian immunodeficiency viruses of stump-tailed macaques
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