TRIM5 Suppresses Cross-Species Transmission of a Primate Immunodeficiency Virus and Selects for Emergence of Resistant Variants in the New Species

Abstract

Cross-species transmission of simian immunodeficiency virus from sooty mangabeys (SIVsm) into rhesus macaques, and subsequent emergence of pathogenic SIVmac, required adaptation to overcome restriction encoded by the macaque TRIM5 gene.

Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction

“…82 It is also used to induce AIDS-like disease in rhesus macaques, although the degree of pathogenicity and viremia induced by this strain is highly variable. 75,82 Similar to the Lim study, this study also observed that SIVsmE543-3 replication in rhesus macaques is modulated by individual TRIM5a alleles. 75 By following the replication of virus in these animals over an extended period, the emergence of a TRIM5a-resistant strain of this virus in infected macaques that were originally able to control viral replication quite well was also noted.…”

“…75 By following the replication of virus in these animals over an extended period, the emergence of a TRIM5a-resistant strain of this virus in infected macaques that were originally able to control viral replication quite well was also noted. 75 Taken together, these two studies demonstrate that allelic diversity of the TRIM5a gene has the potential to differentially modulate the replication of viruses that individuals within a species may encounter.…”

“…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.…”

“…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. 82 It is also used to induce AIDS-like disease in rhesus macaques, although the degree of pathogenicity and viremia induced by this strain is highly variable.…”

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes

“…Understanding when these adaptive changes occurred, together with how they altered the antiviral specificities of these genes, can lead to strong inferences about the existence of ancient viruses and their consequences on the modern function and specificity of the primate innate immune system. For example, although the TRIM5α protein encodes a retroviral restriction factor that blocks the viral life cycle of several retroviruses (3)(4)(5)(6)(7)(8), retroviral specificity varies among primates as a result of ancient selection for changes in antiviral specificity (9)(10)(11)(12). These species-specific differences in TRIM5α are due to dramatic variation in both the coiled-coil and B30.2 domains, which are responsible for the interaction with the viral capsid protein of a variety of retroviruses (13,14).…”