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Posted: 13 Oct 2011
30 years in 30 weeks, 2004

Members of the intrinsic immune system (see also year 2002 of this series), TRIM proteins, inhibit viruses in a species-specific manner – when crossing from one host specie to another, viruses have to adapt their capsid proteins to avoid detection by these restriction factors. Recent studies of TRIM proteins in different species and of their interaction with retroviruses uncovered fascinating stories of evolutionary interplay between viruses and their hosts. In their commentary, Drs. Sodroski and Stremlau describe the discovery of TRIM5alpha, which inhibits replication of HIV in non-human primates.

The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.
Nature. 2004 Feb 26;427(6977):848-53.
Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J.

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Commentary by Drs. Sodroski and Stremlau

Dr. Sodroski (left) and Dr. Stremlau (right)
This paper identified a protein, TRIM5alpha, as a host cell factor that prevents HIV-1 from establishing infection in the cells of Old World monkeys.  This novel host restriction factor appeared to act just after virus entry by targeting the HIV-1 capsid and disrupting reverse transcription.  Although the TRIM5alpha protein from Old World monkeys potently blocked HIV-1 infection, the human TRIM5alpha protein was much less active against HIV-1; thus, the paper demonstrated that species-specific differences in TRIM5alpha could influence the efficacy of this restriction factor against particular retroviruses.

The paper represented the culmination of a long and intensive search for this restriction factor by several laboratories.  The existence of such a factor was predicted by earlier studies that attempted to create animal models of HIV-1 infection. Although HIV-1 is thought to have evolved from simian immunodeficiency viruses (SIVs), unlike SIV, HIV-1 cannot infect Old World monkeys.  Initial studies led to the realization that the basis for HIV-1’s inability to infect Old World monkey cells resided in its capsid, the protein shell that surrounds the viral RNA and replication machinery in the virion.  Viruses with HIV-1 capsids were found to encounter a block in Old World monkey cells soon after entry.  Studies from the laboratories of Paul Bieniasz, Greg Towers and Ned Landau suggested that this block was mediated by a dominant factor, and the search for this host factor began in earnest.

One of us, Matthew Stremlau, took on the daunting task of establishing a screen that could pluck the relevant gene for this factor from a monkey cDNA library.  Several years earlier, Jonathan Stoye’s laboratory identified the first retroviral restriction factor, Fv1.  The messenger RNA coding for Fv1 is present in cells at extremely low levels.  We worried that the gene we were looking for might also not be well-represented in our cDNA libraries.  We also had little information about the kind of factor we were looking for.  Fv1, for example, was derived from an endogenous retrovirus.  Were we looking for a human or retroviral gene product?  After nearly a year of trying various screening strategies, we finally identified several cell clones that exhibited a strong and specific block to HIV-1. The first HIV-1-resistant clone expressed multiple cDNAs, one of them being TRIM5.  However, the very limited information available on TRIM proteins at the time led us to put the clone back in the freezer while we kept searching.  When we found a second HIV-1-restricting clone that expressed TRIM5, we started to focus on the possibility that TRIM5alpha was the desired restriction factor.  Finally, when we knocked TRIM5 down in Old World monkey cells, the results were stunning – the block to HIV-1 infection was gone! 

TRIM5alpha is a member of a large but poorly understood family of proteins, the tripartite motif (TRIM) proteins. Initially we thought that TRIM5alpha might be an uncoating factor; perhaps in the Old World monkey lineage, TRIM5 had acquired a mutation that caused the protein to function improperly.  However, we soon found that knockdowns of TRIM5alpha in human cells didn’t attenuate HIV-1 replication.  Thus, TRIM5alpha appeared to be a potent – and highly specific – antiviral factor.  Of immediate interest was the observation that many TRIM proteins are dimers and contain C-terminal domains with substantial variability; in some ways, TRIM5alpha resembles an intracellular antibody with specificity for particular retroviral capsids.  The TRIM5alpha proteins in different mammalian species have been subsequently shown to restrict infection by several diverse types of retroviruses, and even some herpesviruses.  Unfortunately for humans, several million years ago, when we shared a common ancestor with chimpanzees, our TRIM5alpha protein underwent a specific change resulting in the introduction of an arginine residue in a particular place. This mutation rendered our TRIM5alpha protein relatively ineffective in blocking HIV-1; were it not for this single mutation, there likely would be no AIDS epidemic today!  Without this mutation, human TRIM5alpha is a very potent HIV-1 restriction factor; hence, ways to activate the protective activity of human TRIM5alpha are being investigated.

Although TRIM5alpha exerts only a minimal impact on the current HIV-1 epidemic in humans, this protein has helped shape the species-specific spread of SIVs in African monkeys.  Moreover, differences in TRIM5alpha proteins among individual monkeys within a species can influence the efficiency with which these animals acquire infection after exposure to SIV.

Finally, TRIM proteins other than TRIM5 have been reported to contribute to cellular resistance to a number of viruses, either by interactions with viral components or by regulation of other proteins involved in innate immunity.  Future studies of this fascinating family of proteins will no doubt reveal other surprising relationships.

About the authors:
Joseph Sodroski is a professor in the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School.
Matthew Stremlau is a postdoctoral researcher in the laboratory of Pardis Sabeti in the Center for Systems Biology at Harvard University.

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