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Impact of TRIM5? in vivo.

ABSTRACT: HIV type 1 (HIV-1) has a very narrow host range that is limited to humans and chimpanzees. HIV-1 cannot replicate well in Old World monkey cells such as rhesus and cynomolgus monkeys. Tripartite motif (TRIM)5? is a key molecule that confers potent resistance against HIV-1 infection and is composed of really interesting new gene, B-box2, coiled-coil and PRYSPRY domains. Interaction between TRIM5? PRYSPRY domains and HIV-1 capsid core triggers the anti-HIV-1 activity of TRIM5?. Analysis of natural HIV variants and extensive mutational experiments has revealed the presence of critical amino acid residues in both the PRYSPRY domain and HIV capsid for potent HIV suppression by TRIM5?. Genetic manipulation of the human TRIM5 gene could establish human cells totally resistant to HIV-1, which may lead to a cure for HIV-1 infection in the future.

SUBMITTER: Nakayama EE

PROVIDER: S-EPMC4568895 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Impact of TRIM5α in vivo.

Nakayama Emi E EE Shioda Tatsuo T

AIDS (London, England) 20150901 14

HIV type 1 (HIV-1) has a very narrow host range that is limited to humans and chimpanzees. HIV-1 cannot replicate well in Old World monkey cells such as rhesus and cynomolgus monkeys. Tripartite motif (TRIM)5α is a key molecule that confers potent resistance against HIV-1 infection and is composed of really interesting new gene, B-box2, coiled-coil and PRYSPRY domains. Interaction between TRIM5α PRYSPRY domains and HIV-1 capsid core triggers the anti-HIV-1 activity of TRIM5α. Analysis of natural ...[more]

PMID: 26372380

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Project description:All genes in the TRIM6/TRIM34/TRIM5/TRIM22 locus are type I interferon inducible, with TRIM5 and TRIM22 possessing antiviral properties. Evolutionary studies involving the TRIM6/34/5/22 locus have predominantly focused on the coding sequence of the genes, finding that TRIM5 and TRIM22 have undergone high rates of both non-synonymous nucleotide replacements and in-frame insertions and deletions. We sought to understand if divergent evolutionary pressures on TRIM6/34/5/22 coding regions have selected for modifications in the non-coding regions of these genes and explore whether such non-coding changes may influence the biological function of these genes. The transcribed genomic regions, including the introns, of TRIM6, TRIM34, TRIM5, and TRIM22 from ten Haplorhini primates and one prosimian species were analyzed for transposable element content. In Haplorhini species, TRIM5 displayed an exaggerated interspecies variability, predominantly resulting from changes in the composition of transposable elements in the large first and fourth introns. Multiple lineage-specific endogenous retroviral long terminal repeats (LTRs) were identified in the first intron of TRIM5 and TRIM22. In the prosimian genome, we identified a duplication of TRIM5 with a concomitant loss of TRIM22. The transposable element content of the prosimian TRIM5 genes appears to largely represent the shared Haplorhini/prosimian ancestral state for this gene. Furthermore, we demonstrated that one such differentially fixed LTR provides for species-specific transcriptional regulation of TRIM22 in response to p53 activation. Our results identify a previously unrecognized source of species-specific variation in the antiviral TRIM genes, which can lead to alterations in their transcriptional regulation. These observations suggest that there has existed long-term pressure for exaptation of retroviral LTRs in the non-coding regions of these genes. This likely resulted from serial viral challenges and provided a mechanism for rapid alteration of transcriptional regulation. To our knowledge, this represents the first report of persistent evolutionary pressure for the capture of retroviral LTR insertions.

Project description:Human immunodeficiency virus (HIV) has a very narrow host range. HIV type 1 (HIV-1) does not infect Old World monkeys, such as the rhesus monkey (Rh). Rh TRIM5? was identified as a factor that confers resistance, intrinsic immunity, to HIV-1 infection. Unfortunately, human TRIM5? is almost powerless to restrict HIV-1. However, human TRIM5? potently restricts N-tropic murine leukemia viruses (MLV) but not B-tropic MLV, indicating that human TRIM5? represents the restriction factor previously designated as Ref1. African green monkey TRIM5? represents another restriction factor previously designated as Lv1, which restricts both HIV-1 and simian immunodeficiency virus isolated from macaque (SIVmac) infection. TRIM5 is a member of the tripartite motif family containing RING, B-box2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase, and TRIM5? is thought to degrade viral core via ubiquitin-proteasome-dependent and -independent pathways. The alpha isoform of TRIM5 has an additional C-terminal PRYSPRY domain, which is a determinant of species-specific retrovirus restriction by TRIM5?. On the other hand, the target regions of viral capsid protein (CA) are scattered on the surface of core. A single amino acid difference in the surface-exposed loop between ?-helices 6 and 7 (L6/7) of HIV type 2 (HIV-2) CA affects viral sensitivity to human TRIM5? and was also shown to be associated with viral load in West African HIV-2 patients, indicating that human TRIM5? is a critical modulator of HIV-2 replication in vivo. Interestingly, L6/7 of CA corresponds to the MLV determinant of sensitivity to mouse factor Fv1, which potently restricts N-tropic MLV. In addition, human genetic polymorphisms also affect antiviral activity of human TRIM5?. Recently, human TRIM5? was shown to activate signaling pathways that lead to activation of NF-?B and AP-1 by interacting with TAK1 complex. TRIM5? is thus involved in control of viral infection in multiple ways.

Dataset Information

Impact of TRIM5? in vivo.

Publications

Impact of TRIM5α in vivo.

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