Abstract
TRIM5α is a restriction factor that limits infection of human cells by so-called N- but not B- or NB-tropic strains of murine leukemia virus (MLV). Here, we performed a mutation-based functional analysis of TRIM5α-mediated MLV restriction. Our results reveal that changes at tyrosine336 of human TRIM5α, within the variable region 1 of its C-terminal PRYSPRY domain, can expand its activity to B-MLV and to the NB-tropic Moloney MLV. Conversely, we demonstrate that the escape of MLV from restriction by wild-type or mutant forms of huTRIM5α can be achieved through interdependent changes at positions 82, 109, 110, and 117 of the viral capsid. Together, our results support a model in which TRIM5α-mediated retroviral restriction results from the direct binding of the antiviral PRYSPRY domain to the viral capsid, and can be prevented by interferences exerted by critical residues on either one of these two partners.
Highlights
Retroelements constitute important evolutionary forces for the genome of higher organisms, yet their uncontrolled spread, whether from endogenous loci or within the context of retroviral infections, can cause diseases such as cancer, autoimmunity and immunodeficiency, including acquired immunodeficiency syndrome (AIDS)
In order to characterize the interaction between huTRIM5a and its viral targets, we introduced amino acid changes in the central V1 region of its PRYSPRY domain
Albeit not yet formally demonstrated, that tripartite motif 5a (TRIM5a)-mediated retroviral restriction proceeds through the direct binding of the antiviral PRYSPRY domain to the capsid of incoming viruses [13,17,18,24,27]
Summary
Retroelements constitute important evolutionary forces for the genome of higher organisms, yet their uncontrolled spread, whether from endogenous loci or within the context of retroviral infections, can cause diseases such as cancer, autoimmunity and immunodeficiency, including AIDS. The product of the Friend virus susceptibility 1 (Fv1) gene, which shares similarity with the gag region of an endogenous retrovirus, conditions the susceptibility of various mouse strains to murine leukemia virus (MLV) [2,3]. N-tropic and Btropic MLV strains replicate in Swiss/NIH and in Balb/c mice, respectively, reflecting the presence of either the n or the b allele of Fv1 in the genome of these animals. Moloney MLV (Mo-MLV) harbors an alanine at this position and escapes both Fv1n and Fv1b, is termed NB-tropic
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