TRIM5α Modulates Immunodeficiency Virus Control in Rhesus Monkeys

Abstract

The cytoplasmic TRIM5α proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5α proteins of the natural hosts. To address whether TRIM5α contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5α cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5α B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys to SIVmac infection. We also show the importance in vivo of the interaction of SIVmac with different allelic forms of TRIM5, demonstrating that particular alleles are associated with as much as 1.3 median log difference in set-point viral loads in SIVmac-infected rhesus monkeys. Moreover, these allelic forms of TRIM5 were associated with the extent of loss of central memory (CM) CD4+ T cells and the rate of progression to AIDS in the infected monkeys. These findings demonstrate a central role for TRIM5α in limiting the replication of an immunodeficiency virus infection in a primate host.

Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques

“…A high frequency (97.5%) of this mutation was detected in the CE macaque population, indicating that this deletion has become virtually fixed in the CE macaque. By contrast, in the CR macaque population, the frequency of this mutation is about 50%, only marginally higher than in the IR macaque population (36%) 17 . The variation in frequency of this 6-bp deletion and of other polymorphisms between macaques of different geographic origins may well be responsible for the observed differences in HIV resistance between these macaque species/subspecies 16 .…”

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

“…[79][80][81] Critically, not only did intraspecies allelic differences affect restriction of SIVmac239 in single cycle infectivity assays, these differences also conferred altered susceptibility to critical aspects of AIDS-like disease progression, including peak and set-point plasma RNA levels, CD4 T cell depletion, and survival. 76 Another similar study by Kirmaier et al found that many of the same rhTRIM5a alleles examined in the Lim study also differentially affected the replication of another commonly used laboratory strain, SIVsmE543-3. 75 This SIV strain is derived from a strain of SIV isolated from sooty mangabeys and experimentally passaged through two rhesus macaques.…”

“…A number of independent studies have examined polymorphisms in rhesus macaques and identified alleles that exhibit significant differences in their ability to restrict diverse retroviruses. [75][76][77][78] One of these studies, by Lim and colleagues, observed significant differences in the ability of different TRIM5a alleles present in these macaques to inhibit infection by SIVmac239, a viral strain commonly used to infect rhesus macaques to induce an AIDS-like disease in studies of AIDS pathogenesis and vaccine strategies. [79][80][81] Critically, not only did intraspecies allelic differences affect restriction of SIVmac239 in single cycle infectivity assays, these differences also conferred altered susceptibility to critical aspects of AIDS-like disease progression, including peak and set-point plasma RNA levels, CD4 T cell depletion, and survival.…”

“…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).…”

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