The TRIM5α 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.Lentiviruses and their hosts have been interacting and adapting to each other for millions of years. Humans and nonhuman primates, like other mammals, express cellular restriction factors to inhibit viral replication (6). These restriction factors offer protection against a broad range of viruses and represent an important barrier to zoonotic transmissions. Recently, three major classes of retroviral restriction factors have been identified: APOBEC3, tripartite motif protein 5 alpha (TRIM5␣), and tetherin (12,16,19,20). Each of these factors targets a different step in the virus life cycle to suppress viral replication. To counteract these restriction factors, primate lentiviruses have developed a series of accessory proteins that, in part, circumvent their actions and allow viruses to efficiently replicate (11).Polymorphic alleles at the rhesus macaque TRIM5 locus correlate with a 1.3-to 3-log reduction in simian immunodeficiency virus (SIV) replication (7, 10). The mechanism by which TRIM5␣ affects viral replication is unclear, but it appears to act by binding incoming viral capsids and mediating premature viral uncoating (18). A recent study also suggests a role for TRIM5 mediating the early, innate immune response to retroviral infection (14). Rhesus macaque TRIM5 is polymorphic, and the encoded protein includes a TRIM5-cyclophilin A (CypA) chimera in which CypA replaced the TRIM5␣ binding domain (7,10,13,17,19 ) had intermediate plasma viral loads. A less dramatic effect on plasma virus replication was also seen in a cohort of SIVmac251-infected animals by using similar TRIM5 groupings (10).

Susceptibility to Repeated, Low-Dose, Rectal SHIVSF162P3 Challenge Is Independent of TRIM5 Genotype in Rhesus Macaques

“…15 The alleles did not impact SIV mac239 14 RLD rectal acquisition, although an effect on SIV mac251 replication after intravenous acquisition was found. 16,25 Contrary to SIV smE660 challenges, we found no evidence that Q alleles conferred increased susceptibility or that TFP and CypA alleles conferred resistance to SHIV SF162P3 infection.…”

“…Previous work has provided evidence that TRIM5 alleles affect SIV smE660 RLD rectal acquisition 14 and penile acquisition. 15 The alleles did not impact SIV mac239 14 RLD rectal acquisition, although an effect on SIV mac251 replication after intravenous acquisition was found.…”

“…These percentages were similar to distributions recently reported from another major U.S. facility for nonhuman primate research. 13,14 The median number of exposures required for infection was three (TRIM5 Q/Q ), four (TRIM5 Q/CypA ), three (TRIM5 TFP/Q ), three (TRIM5 TFP/TFP ), and two (TRIM5 TFP/CypA ) (Fig. 1).…”

“…9,11,12 In rhesus macaques, TRIM5 gene variants can be grouped into three allelic classes, TRIM5 Q , TRIM5 CypA , and TRIM5 TFP , which yield six possible genotypes: TRIM5 TFP/TFP , TRIM5 TFP/Q TRIM5 Q/Q , TRIM5 Q/CypA , and TRIM5 CypA/CypA . Cell culture assays and animal infections have been used to elucidate the role that allelic variation in the rhesus macaque TRIM5 gene has in susceptibility to SIV infection and viral replication, [13][14][15][16] while other species such as cynomolgus macaques are also under investigation. 17 The goal of this study was to define the influence of the TRIM5 genotype on susceptibility to SHIV SF162P3 infection in a RLD model.…”

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

“…1B). Because the TRIM5α genotype was reported to affect viremia after infection by SIVsmE660 (13), statistical analyses were performed after stratification to control for the restrictive TRIM5α genotype relative to the susceptible and moderate restrictive genotypes of the enrolled animals ( Table S2). The analysis of virus acquisition was performed by combining all vaccinees (n = 24) (Fig.…”