A clue from macaques yields evidence for impaired retroviral defense genes in humans

Researchers Harmit Malik and Michael Emerman and colleagues at the Fred Hutchinson Cancer Research Center have found that a surprisingly large fraction of humans may be impaired in the function of a recently discovered arm of the body's defense against invading retroviruses such as HIV.

One of the key components of this "intrinsic immunity" is encoded by the TRIM5 gene. This gene was discovered because the version of TRIM5 possessed by rhesus macaques allows them to resist HIV infection, whereas the human version does not. Instead, the human version appears to respond to evolutionarily older viruses that are related to now-extinct viruses that are resident in the human genome.

Previous studies had suggested that relatively few evolutionary changes in the TRIM5 protein were responsible for this difference in battling retroviral infection. This prompted the Malik and Emerman groups to screen human populations for slightly altered versions of TRIM5 that might be able to resist HIV infection.

Unexpectedly, the researchers found a single mutation in TRIM5 that impairs its ability to defend against retroviruses. This mutation occurs at a very high frequency in some ethnic groups, leading the authors to conclude that past periods in human history corresponding to relatively low levels of retroviral infections may have allowed impaired versions of retroviral defense genes--such as the hobbled version of TRIM5--to arise and thrive. As a consequence, the abundance of this impaired gene may have deleterious effects on the ability of present-day humans to ward off infections by both old and new retroviruses.


The researchers include Sara L. Sawyer, Lily I. Wu, Michael Emerman, and Harmit S. Malik of the Fred Hutchinson Cancer Research Center in Seattle, WA; Joshua M. Akey of the University of Washington in Seattle, WA. This work was supported by National Institutes of Health grants R37 AI30927 (M.E.) and T32 CA 09657 (S.L.S.), by the Division of Nutritional Sciences and the Center for Ecogenetics and Environmental Health at the University of Washington (J.M.A.), and by startup funds from the Fred Hutchinson Cancer Research Center, a Searle Scholar Award and an Alfred P. Sloan Fellowship (H.S.M.).

Sawyer et al.: "High Frequency Persistence of an Impaired Allele of the Retroviral Defense Gene TRIM5 in Humans." Publishing in Current Biology Vol. 16, Issue 1, pages 95-100, January 10, 2006. DOI 10.1016/j.cub.2005.10.045, www.current-biology.com

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