Genetic Association of the Antiviral Restriction Factor TRIM5α with Human Immunodeficiency Virus Type 1 Infection

Abstract

The innate antiviral factor TRIM5␣ restricts the replication of some retroviruses through its interaction with the viral capsid protein, leading to abortive infection. While overexpression of human TRIM5␣ results in modest restriction of human immunodeficiency virus type 1 (HIV-1), this inhibition is insufficient to block productive infection of human cells. We hypothesized that polymorphisms within TRIM5 may result in increased restriction of HIV-1 infection. We sequenced the TRIM5 gene (excluding exon 5) and the 4.8-kb 5 putative regulatory region in genomic DNA from 110 HIV-1-infected subjects and 96 exposed seronegative persons, along with targeted gene sequencing in a further 30 HIV-1-infected individuals. Forty-eight single nucleotide polymorphisms (SNPs), including 20 with allele frequencies of >1.0%, were identified. Among these were two synonymous and eight nonsynonymous coding polymorphisms. We observed no association between TRIM5 polymorphism in HIV-1-infected subjects and their set-point viral load after acute infection, although one TRIM5 haplotype was weakly associated with more rapid CD4 ؉ T-cell loss. Importantly, a TRIM5 haplotype containing the nonsynonymous SNP R136Q showed increased frequency among HIV-1-infected subjects relative to exposed seronegative persons, with an odds ratio of 5.49 (95% confidence interval ‫؍‬ 1.83 to 16.45; P ‫؍‬ 0.002). Nonetheless, we observed no effect of individual TRIM5␣ nonsynonymous mutations on the in vitro HIV-1 susceptibility of CD4 ؉ T cells. Therefore, any effect of TRIM5␣ polymorphism on HIV-1 infection in primary lymphocytes may depend on combinations of SNPs or on DNA sequences in linkage disequilibrium with the TRIM5␣ coding sequence.

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

“…73 However, another study did not observe a statistically significant difference in viral set point in patients homozygous for this allele, although the trend seems visible despite a small number of individuals within the H43Y patient population analyzed. 74 Similarly neutral observations have been made for other common SNPs present within the human population, including V112F, R136Q, E238W, G249D, and H419Y. Although some of these SNPs have, in individual studies, shown some small alteration of susceptibility to HIV-1 infection, these appear to be spurious, as other studies examining the same SNP have failed to confirm the small differences observed in some individual studies.…”

“…In humans, the majority of polymorphisms occur within the RBCC motif in regions of the protein that are not thought to be responsible for modulating TRIM5a specificity to individual retroviruses. [70][71][72]74 Conversely, almost all of the nonsynonymous SNPs identified in rhesus macaques are located in the SPRY and CC domains, [75][76][77][78] which are the regions of the protein reported to dictate the specificity of TRIM5a restriction (Fig. 2).…”

“…Although some of these SNPs have, in individual studies, shown some small alteration of susceptibility to HIV-1 infection, these appear to be spurious, as other studies examining the same SNP have failed to confirm the small differences observed in some individual studies. [70][71][72][73][74] FIG. 2.…”

Molecular evolution of the antiretroviral TRIM5 gene

“…Studies using these cohorts have sought associations between variation in TRIM5 and a variety of outcomes, such as (a) susceptibility/resistance to HIV-1 infection (by measuring allele frequencies in high-risk yet uninfected individuals), (b) levels of viral replication in HIV-1-infected individuals, and (c) various indicators of disease progression among HIV-1-infected individuals. Most studies have reported weak associations with at least one of these outcomes, although these independent studies did not arrive at the same conclusions (Goldschmidt et al 2006;Javanbakht et al 2006;Nakayama et al 2007;Speelmon et al 2006;van Manen et al 2008). Further work will be required to determine the source of the discrepancies, and whether these reflect true biological/genotypic differences between cohorts.…”

“…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).…”