The Effect of Trim5 Polymorphisms on the Clinical Course of HIV-1 Infection

Abstract

The antiviral factor tripartite interaction motif 5α (Trim5α) restricts a broad range of retroviruses in a species-specific manner. Although human Trim5α is unable to block HIV-1 infection in human cells, a modest inhibition of HIV-1 replication has been reported. Recently two polymorphisms in the Trim5 gene (H43Y and R136Q) were shown to affect the antiviral activity of Trim5α in vitro. In this study, participants of the Amsterdam Cohort studies were screened for polymorphisms at amino acid residue 43 and 136 of the Trim5 gene, and the potential effects of these polymorphisms on the clinical course of HIV-1 infection were analyzed. In agreement with the reported decreased antiviral activity of Trim5α that contains a Y at amino acid residue 43 in vitro, an accelerated disease progression was observed for individuals who were homozygous for the 43Y genotype as compared to individuals who were heterozygous or homozygous for the 43H genotype. A protective effect of the 136Q genotype was observed but only after the emergence of CXCR4-using (X4) HIV-1 variants and when a viral load of 104.5 copies per ml plasma was used as an endpoint in survival analysis. Interestingly, naive CD4 T cells, which are selectively targeted by X4 HIV-1, revealed a significantly higher expression of Trim5α than memory CD4 T cells. In addition, we observed that the 136Q allele in combination with the −2GG genotype in the 5′UTR was associated with an accelerated disease progression. Thus, polymorphisms in the Trim5 gene may influence the clinical course of HIV-1 infection also underscoring the antiviral effect of Trim5α on HIV-1 in vivo.

Molecular evolution of the antiretroviral TRIM5 gene

“…The discovery of extensive diversity in TRIM5 between primate species begged the question of whether the locus would be polymorphic within species as well, and whether naturally occurring variants differentially affect susceptibility to retroviral infection or disease progression. Thus far, reports of extensive within-species sampling for polymorphism in TRIM5 have been limited to humans (Sawyer et al 2006), most commonly in the context of HIV/AIDS cohorts (Goldschmidt et al 2006;Javanbakht et al 2006;Nakayama et al 2007;Speelmon et al 2006;van Manen et al 2008), and two species of Old World monkey ( Fig. 5; Newman et al 2005;Wilson et al 2008a).…”

“…Of the common protein-altering SNPs, only one (H43Y) was found to modulate activity against retroviruses in vitro; in this case, the 43Y allele weakens TRIM5α restriction (Sawyer et al 2006). This study brought H43Y forward as a candidate SNP for differential susceptibility of certain human populations, and at least one study has reported an association between the 43Y/Y genotype and accelerated disease progression (van Manen et al 2008). It will be especially interesting to explore the effects of TRIM5 genotype in cohorts from Central and South America, where the 43Y…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…Studies examining this question have produced conflicting results thus far. Polymorphisms in the Trim5a gene [95] and different expression levels of APOBEC3G [96] are associated with greater control of infection. However, this result has not been confirmed by other studies [97,98], and the expression of IFN-induced restriction factors may also be driven by viral replication [99].…”

Innate Barriers to Viral Infection

“…future science group Expression differences and TRIM5 polymorphisms influence rates of HIV-1 acquisition and/or disease progression [16]. Moreover, TRIM5 in nonhuman primates also plays an important role in limiting transmission of SIVs and in controlling the outcome of infection with these viruses [17].…”