14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 3d)

Harmit Malik and M Emerman
Fred Hutchinson Cancer Res Ctr, Seattle, WA, US

BACKGROUND: The recent discoveries of intrinsic restriction mechanisms against HIV have focused attention on the arsenal of strategies that primates have employed to defend against these invasions. These strategies often involve a direct interaction between the host encoded antiviral proteins and viral proteins. The single-stranded DNA editing enzyme APOBEC3G was discovered by virtue of its ability to restrict a vif-deficient HIV-1 virus, and APOBEC3G interactions with gag-encoded proteins ensure the packaging of the editing enzyme into the viral capsid, but avoiding interaction with the viral accessory protein vif is as important to prevent proteolytic degradation. Similarly, the cytoplasmic protein TRIM5α was discovered because it conferred restrictive ability against HIV-1 to rhesus cells and TRIM5α’s viral capsid-binding discriminative domain determines its antiviral specificity. Antagonistic proteins locked in such conflicts frequently are predicted to be subject to rapid evolution, as one protein evolves to avoid interactions while the other evolves to restore them (referred to as “the Red Queen” hypothesis). We find that both APOBEC3G as well as TRIM5α have been subject to such rapid evolution. Unexpectedly, these episodes of rapid evolution date back to (or before) the evolutionary origin of primates (~35 million years), much before the origin of lentiviruses like HIV-1. Thus, in spite of the fact that both APOBEC3G and TRIM5α were discovered because of their anti-HIV effect, the constant evolutionary pressure imposed by endogenous retroviruses mobilizing in primate germ lines is likely responsible for their rapid evolution and species-specificity. We have been able to use the signature of rapid evolution to identify a small “patch” in the TRIM5α protein that is responsible for antiviral specificity, highlighting the power of such evolutionary analyses. Screening human populations for genetic variation in TRIM5α we uncovered an impaired allele at an unexpectedly high frequency (~50%) in certain ethnic groups.

CONCLUSIONS: We can use the evolutionary insights gained from APOBEC3G and TRIM5α as well as human population genetics to identify other, novel restriction factors employed for retroviral defense by primate genomes. I will describe our techniques and studies for such identifications.

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2007-02-25
3d

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