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Multitasking Protein—Nature’s Defense Against Retroviruses

 
  July, 19 2004 14:05
your information resource in human molecular genetics
 
     
Mammalian cells have evolved an arsenal of genes that fend off invading retroviruses and inhibit cross-species transmission. Three new studies converge upon a recently identified cellular protein, TRIM5alpha, as a factor that might account for a large part of this broad-spectrum antiviral activity. TRIM5alpha was first identified earlier this year as a gene responsible for blocking HIV-1 infection in rhesus monkeys, helping to explain why some primates are resistant to infection by HIV. However, at that time, TRIM5alpha did not appear to block infection with other types of retroviruses, specifically the murine leukemia virus (MLV) for which human restriction activity had been observed. Now, reports from three different laboratories suggest that TRIM5alpha actually has much broader antiretroviral activity than previously shown, and, as such, may be a key player in innate immunity against many types of retroviruses. Paul Bieniasz and colleagues from the Aaron Diamond AIDS Research Center report that the human, rhesus monkey, and African green monkey forms of TRIM5alpha have wide-ranging antiretroviral activities. Specifically, all three species were able to inhibit infection with MLV, a mouse retrovirus, as well as virus from horses called equine infectious anemia virus (EIAV). However, only the monkey forms, and not the human form, of TRIM5alpha could block HIV-1 infection. African green monkey TRIM5alpha emerged as a superpower, with activity against a wide range of retroviruses that had little genetic similarity.

Greg Towers and colleagues from University College London report similar findings, but additionally link the activity of the mouse restriction factor Fv1 to TRIM5alpha expression. Also, they identified a genetic variation between rhesus and green monkey TRIM5alpha sequences—an extra 18 amino acids in the green monkey form—which may explain why the green monkey TRIM5alpha has a much broader antiviral activity than the human and rhesus forms.

The findings of Jonathan Stoye and colleagues at the British National Institute for Medical Research in article 2876 echo the above, reporting that TRIM5alpha isolated from African green monkeys, rhesus monkeys, and humans were all potent blockers of MLV infection. Only the African green monkey and rhesus forms of TRIM5alpha restricted HIV infection. In addition, they found that another member of the TRIM family, TRIM1, from humans and green monkeys could also restrict MLV, suggesting that other members of the TRIM family of proteins might also be important for innate immunity against viral infection.

Together, these three new studies suggest that TRIM5alpha is an ancient component of the mammalian immune response and represents a molecular wall that retroviruses must scale in order to infect a new species. Such research may help identify new approaches to combating retroviruses, like HIV.

"Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5alpha" by Theodora Hatziioannou, David Perez-Caballero, Annie Yang, Simone Cowan, and Paul D. Bieniasz

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"The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities" by Zuzana Keckesova, Laura M. J. Ylinen, and Greg J. Towers

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"TRIM5alpha protein restricts both HIV-1 and murine leukemia virus" by Melvyn W. Yap, Sebastien Nisole, Clare Lynch, and Jonathan P. Stoye

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Copyright © 2004 by the National Academy of Sciences


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