Schaller, T.; (2009) Characterisation of TRIM5α and related retroviral restriction factors. Doctoral thesis , UCL (University College London).

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Abstract

Retroviruses possess an RNA genome that is reverse transcribed into DNA and becomes integrated into the host genome during infection. Human immunodeficiency virus 1 (HIV-1) belongs to the genus lentivirus of the retroviridae family and is a major human pathogen with more than 50 million infected people worldwide to date. Lentiviruses have very narrow host ranges. Cross-species lentiviral transmissions are rare, due to the ability of mammals to counteract viral infections by the innate immune system, which includes intracellular factors that block virus replication. Of these, the murine protein Fv1 and the tripartite (RBCC) motif protein family member TRIM5α potently inhibit retroviral infections early after virus cell entry. This study presents evidence that antiviral activity exerted by TRIM5α is conserved across mammals. Rabbit cells are strongly non-permissive to infections by certain retroviruses including HIV-1. The study identifies a TRIM5α orthologue in rabbits, which possesses antiretroviral activity. Phylogenetic analysis demonstrates that rabbit TRIM5 is a true orthologue and clusters with other mammalian TRIM5 genes. Remarkably, TRIM5 fusion proteins with the prolyl-peptidyl isomerase cyclophilin A (CypA) have independently evolved twice by retrotransposition of a CypA cDNA into the TRIM5 genomic locus, generating a viral restriction factor with a CypA binding domain. This study shows that CypA fusion proteins with RBCC domains of other TRIM proteins also function as restriction factors against HIV-1. Furthermore, fusion of CypA to Fv1 enables the restriction of HIV-1 and FIV. Insights into the mechanism of TRIM5α restriction are also provided in this study. Functional analyses of TRIM5α and TRIMCyp deletion mutants, as well as fusion proteins of Fv1Cyp with the TRIM5α RING and B-box domains, indicate that the RING and B-box domains mediate the proteasome dependent block to reverse transcription during TRIM5α/TRIMCyp restriction. The results suggest that the major antiviral activity exerted by TRIM5α is a RING dependent block to reverse transcription, whereas the major activity of TRIMCyp is independent of RING function.

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