Recent insights into the mechanism and consequences of TRIM5α retroviral restriction

Abstract

The cellular factor TRIM5α inhibits infection by numerous retroviruses in a species-specific manner. The TRIM5α protein from rhesus macaques (rhTRIM5α) restricts infection by HIV-1 while human TRIM5α (huTRIM5α) restricts infection by murine leukemia virus (MLV). In owl monkeys a related protein TRIM-Cyp restricts HIV-1 infection. Several models have been proposed for retroviral restriction by TRIM5 proteins (TRIM5α and TRIM-Cyp). These models collectively suggest that TRIM5 proteins mediate restriction by directly binding to specific determinants in the viral capsid. Through their ability to self-associate TRIM5 proteins compartmentalize the viral capsid core and mediate its abortive disassembly via a poorly understood mechanism that is sensitive to proteasome inhibitors. In this review, we discuss TRIM5-mediated restriction in detail. We also discuss how polymorphisms within human and rhesus macaque populations have been demonstrated to affect disease progression of immunodeficiency viruses in these species.

FIG. 1.

Model for TRIM5α-mediated retroviral restriction. Following entry of the retroviral core (pink) in the host cell cytoplasm TRIM5 proteins directly bind the retroviral capsid by recognizing specific determinants in the viral capsid. Following binding, the B-box2 and L2 regions mediate high-order multimerization and assembly of individual TRIM5 dimers, respectively, resulting in the formation of a hexameric lattice surrounding the viral core. Given the specificity of the SPRY domain for the viral capsid proteins it is possible that multiple TRIM5 lattices assemble around a single virion. A single TRIM5 lattice (green) is shown for clarity. Proteasomal degradation of TRIM5 proteins then triggers “abortive disassembly” of the viral core. This results in dissociation but not degradation of the capsid proteins keeping the cytosolic capsid levels unchanged. The viral capsid is shown in pink and the TRIM5 lattice is shown in green. Color images available online at www.liebertonline.com/aid.

FIG. 2.

TRIM5α polymorphisms present in humans and rhesus macaques. A summary of the studies examining single nucleotide polymorphisms (SNPs) present in human and rhesus macaque TRIM5a genes. The majority of human SNPs are located within the RBCC motif of TRIM5a in regions not thought to govern retroviral specificity (SNPs above the TRIM5a domain structure). Conversely, rhesus macaque SNPs occur predominantly in those regions of the protein that dictate restriction specificity (SNPs below the TRIM5α domain structure).