The TRIM5 Gene Modulates Penile Mucosal Acquisition of Simian Immunodeficiency Virus in Rhesus Monkeys

Abstract

There is considerable variability in host susceptibility to human immunodeficiency virus type 1 (HIV-1) infection, but the host genetic determinants of that variability are not well understood. In addition to serving as a block for cross-species retroviral infection, TRIM5 was recently shown to play a central role in limiting primate immunodeficiency virus replication. We hypothesized that TRIM5 may also contribute to susceptibility to mucosal acquisition of simian immunodeficiency virus (SIV) in rhesus monkeys. We explored this hypothesis by establishing 3 cohorts of Indian-origin rhesus monkeys with different TRIM5 genotypes: homozygous restrictive, heterozygous permissive, and homozygous permissive. We then evaluated the effect of TRIM5 genotype on the penile transmission of SIVsmE660. We observed a significant effect of TRIM5 genotype on mucosal SIVsmE660 acquisition in that no SIV transmission occurred in monkeys with only restrictive TRIM5 alleles. In contrast, systemic SIV infections were initiated after preputial pocket exposures in monkeys that had at least one permissive TRIM5 allele. These data demonstrate that host genetic factors can play a critical role in restricting mucosal transmission of a primate immunodeficiency virus. In addition, we used our understanding of TRIM5 to establish a novel nonhuman primate penile transmission model for AIDS mucosal pathogenesis and vaccine research.

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.…”

“…15 It is possible that penile or other transmission routes are more susceptible to the impact of TRIM5-mediated effects than during rectal transmission. Kirmaier ) led to lower SIV smE543-3 replication than in homozygous TRIM5 Q/Q macaques.…”

“…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.…”

Protection Afforded by an HIV Vaccine Candidate in Macaques Depends on the Dose of SIVmac251at Challenge Exposure

“…We randomized 40 macaques in 4 groups based on the expression of the major histocompatibility complex class I (MHC-I) associated with protection from high viral replication (Mamu-A*01, Mamu-B*08, and Mamu-B*17) and based on the expression of protective alleles for TRIM5␣ (27)(28)(29). We vaccinated 20 adult macaques with DNA SIV gag, pol, and env genes followed by (30) three immunizations with recombinant ALVAC-SIVgpe (6) expressing the same genes.…”

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

“…Recent epidemiologic evidence has prompted an increase in interest in establishing a penile transmission model. Infection of rhesus macaques with SIVmac251 through penile exposure has been recently reported [53,178]. However, repeated exposure of macaques to a dose of 10 TCID50 (n=5) or 10 3 TCID50 (n=2) over 14 inoculations was insufficient to infect the animals Exposures to a high dose of SIVmac251 (10 5 TCID50) twice within the same day was needed to infect 3 of 5 animals.…”