The TRIM5{alpha} genotype of rhesus macaques affects acquisition of simian immunodeficiency virus SIVsmE660 infection after repeated limiting-dose intrarectal challenge

Abstract

It has recently been shown that polymorphism at the rhesus macaque TRIM5 locus can affect simian immunodeficiency virus (SIV) replication. Here we show that TRIM5 alleles can also affect acquisition of SIVsmE660. Animals coexpressing the TRIM5(TFP) and TRIM5(CypA) alleles took significantly longer to become infected with SIVsmE660, but not SIVmac239, after repeated limiting-dose intrarectal challenge than did animals expressing other TRIM5 allele combinations. Our results indicate that the TRIM5 alleles can be a barrier to productive infection and that this should be taken into account when designing acquisition studies using SIVsmE660 or related viruses.

Fig. 1.

Sequence of SIVsmE660 Gag p27^CA known to affect TRIM5-mediated restriction. Partial sequences of the core nucleocapsid protein amino acids 72 to 101 of the two stocks of SIVsmE660 analyzed in this study are aligned against that of the closely related molecular clone SIVsmE543-3. The putative amino acids affecting restriction mediated by TRIM5^TFP (⁷⁴LPA⁷⁶) and TRIM5^CypA (R⁸³) are highlighted in red. Nonsynonymous variations from the SIVsmE543-3 sequence are color coded by frequency. X indicates a mixed amino acid sequence.

Fig. 2.

Acquisition of SIVsmE660 infection after repeated limiting-dose challenge is affected by TRIM5 genotype. (A) Kaplan-Meier curve analysis of the effects different TRIM5 genotypes have on the rate of acquisition of SIVsmE660 infection after repeated limiting-dose intrarectal challenge. The statistical significance of the rates of infection of the different TRIM5 genotypes was determined by log rank test. (B) A comparison of the numbers of challenges needed to productively infect animals expressing the different TRIM5 genotypes with SIVsmE660. Significance between the rates of infection of animals having the TRIM5^TFP/CypA genotype and the other TRIM5 genotypes was determined by parametric generalized gamma model.

Fig. 3.

Acquisition of SIVmac239 infection after repeated limiting-dose intrarectal challenge is not affected by TRIM5 genotype. The Kaplan-Meier curve analysis revealed no significant differences in the acquisition of SIVmac239 infection after repeated limiting-dose intrarectal challenge among the TRIM5 genotypes. We performed a power analysis and determined that our cohort of SIVmac239 challenged animals had 73% power to detect an effect by the TRIM5^TFP/CypA genotype on acquisition of infection similar to that observed for the cohort of SIVsmE660 challenged animals.