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High-Frequency Persistence of an Impaired Allele of the Retroviral Defense Gene TRIM5α in Humans

2006; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês

10.1016/j.cub.2005.11.045

1879-0445

Sara L. Sawyer, Lily I. Wu, Joshua M. Akey, Michael Emerman, Harmit S. Malik,

Immune Cell Function and Interaction

The intracellular TRIM5α protein successfully inhibits HIV-1 infection in rhesus monkeys, but not in humans [1Stremlau M. Owens C.M. Perron M.J. Kiessling M. Autissier P. Sodroski J. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.Nature. 2004; 427: 848-853Crossref PubMed Scopus (1448) Google Scholar, 2Perron M.J. Stremlau M. Song B. Ulm W. Mulligan R.C. Sodroski J. TRIM5alpha mediates the postentry block to N-tropic murine leukemia viruses in human cells.Proc. Natl. Acad. Sci. USA. 2004; 101: 11827-11832Crossref PubMed Scopus (249) Google Scholar, 3Hatziioannou T. Perez-Caballero D. Yang A. Cowan S. Bieniasz P.D. Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5alpha.Proc. Natl. Acad. Sci. USA. 2004; 101: 10774-10779Crossref PubMed Scopus (315) Google Scholar, 4Keckesova Z. Ylinen L.M. Towers G.J. The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities.Proc. Natl. Acad. Sci. USA. 2004; 101: 10780-10785Crossref PubMed Scopus (290) Google Scholar, 5Yap M.W. Nisole S. Lynch C. Stoye J.P. TRIM5alpha protein restricts both HIV-1 and murine leukemia virus.Proc. Natl. Acad. Sci. USA. 2004; 101: 10786-10791Crossref PubMed Scopus (367) Google Scholar, 6Sayah D.M. Sokolskaja E. Berthoux L. Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1.Nature. 2004; 430: 569-573Crossref PubMed Scopus (529) Google Scholar]. A few amino acids in the virus-interacting SPRY domain [7Sebastian S. Luban J. TRIM5alpha selectively binds a restriction-sensitive retroviral capsid.Retrovirology. 2005; 2: 40Crossref PubMed Scopus (196) Google Scholar] were found to be responsible for most of this anti-viral specificity [8Stremlau M. Perron M. Welikala S. Sodroski J. Species-specific variation in the B30.2(SPRY) domain of TRIM5alpha determines the potency of human immunodeficiency virus restriction.J. Virol. 2005; 79: 3139-3145Crossref PubMed Scopus (304) Google Scholar, 9Yap M.W. Nisole S. Stoye J.P. A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction.Curr. Biol. 2005; 15: 73-78Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10Sawyer S.L. Wu L.I. Emerman M. Malik H.S. Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain.Proc. Natl. Acad. Sci. USA. 2005; 102: 2832-2837Crossref PubMed Scopus (511) Google Scholar], raising the possibility that genetic variation among humans could result in TRIM5α proteins with a spectrum of potencies. We found several nonsynonymous SNPs at the human TRIM5 locus, but only one of these (H43Y) was found to have a significant functional consequence. We demonstrate that H43Y impairs TRIM5α restriction of two distantly related retroviruses. H43Y lies in the RING domain of TRIM5α and may negatively affect its putative E3 ubiquitin ligase activity. This detrimental allele dates back to before the African diaspora and is found at a frequency of 43% in indigenous Central and South Americans. We suggest that relaxed constraint due to a recent period of low retroviral challenge has allowed the deleterious H43Y mutation to persist and even to expand after the bottleneck that occurred upon human migration to the New World. The unexpectedly high frequency of an impaired retroviral restriction allele among humans is likely to have a significant impact on our ability to ward off future retroviral challenges.