TRIM5

Understanding infectious disease pathogenesis and evaluating novel candidate treatment interventions for human use frequently requires prior or parallel analysis in animal model systems. While rodent species are frequently applied in such studies, there are situations where non-human primate (NHP) species are advantageous or required. These include studies of animals that are anatomically more akin to humans, where there is a need to interrogate the complexity of more advanced biological systems or simply reflect susceptibility to a specific infectious agent. The contribution of different arms of the immune response may be addressed in a variety of NHP species or subspecies in specific physiological compartments. Such studies provide insights into immune repertoires not always possible from human studies. However, genetic variation in outbred NHP models may confound, or significantly impact the outcome of a particular study. Thus, host factors need to be considered when undertaking such studies. Considerable knowledge of the impact of host immunogenetics on infection dynamics was elucidated from HIV/SIV research. NHP models are now important for studies of emerging infections. They have contributed to delineating the pathogenesis of SARS-CoV-2/COVID-19, which identified differences in outcomes attributable to the selected NHP host. Moreover, their use was crucial in evaluating the immunogenicity and efficacy of vaccines against COVID-19 and establishing putative correlates of vaccine protection. More broadly, neglected or highly pathogenic emerging or re-emergent viruses may be studied in selected NHPs. These studies characterise protective immune responses following infection or the administration of candidate immunogens which may be central to the accelerated licensing of new vaccines. Here, we review selected aspects of host immunogenetics, specifically MHC background and TRIM5 polymorphism as exemplars of adaptive and innate immunity, in commonly used Old and New World host species. Understanding this variation within and between NHP species will ensure that this valuable laboratory source is used most effectively to combat established and emerging virus infections and improve human health worldwide.

The innate immune system of mammals is formed by a complex web of interacting proteins, which together constitute the first barrier of entry for infectious pathogens. Genes from the E3-ubiquitin ligase tripartite motif (TRIM) family have been shown to play an important role in the innate immune system by restricting the activity of different retrovirus species. For example, TRIM5 and TRIM22, have both been associated with HIV restriction, and are regarded as crucial parts of the antiretroviral machinery of mammals. Our analyses of positive selection corroborate the great significance of these genes for some groups of mammals. However, we also show that many species lack TRIM5 and TRIM22 altogether. By analyzing a large number of mammalian genomes, here we provide the first comprehensive view of the evolution of these genes in eutherians, showcasing that the pattern of accumulation of TRIM genes has been dissimilar across mammalian orders. Our data suggests that these differences are caused by evolutionary plasticity of the immune system of eutherians, which have adapted to use different strategies to combat retrovirus infections. Altogether, our results provide insights into the dissimilar evolution of a representative family of restriction factors, highlighting an example of adaptive and idiosyncratic evolution in the innate immune system.

Tripartite motif containing 5α protein is a factor contributing to intracellular defense mechanisms against human immunodeficiency virus-1 (HIV-1) infection. The studies of TRIM5 variants effects on the risk of HIV-1 infection and the clinical course of disease provided inconclusive results in different ethnic groups. The aim of this study was to investigate the influence of TRIM5 variants on susceptibility to HIV-1 infection and clinical parameters among Polish HIV-1-infected patients.

In our study, we investigated 301 HIV-1-infected patients and 186 age-matched seronegative controls. Seven variants of the TRIM5 gene (rs7127617, rs3824949, rs3740996, rs11601507, rs10838525, rs11038628, and rs28381981) were genotyped using both sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques.

The frequencies of rs7127617 TT genotype and T allele occurrence were lower in HIV-1-infected subjects compared to controls (0.14 vs. 0.26 for T/T genotype and 0.45 vs. 0.54 for T allele), suggesting their possible protective effect (p = 0.005 and p = 0.007, respectively). Heterozygosity and presence of the T allele at rs3740996 were enriched in controls compared to HIV-1-infected group (0.19 vs. 0.12 for C/T genotype and 0.11 vs. 0.07 for T allele; p = 0.03 and p = 0.02, respectively). Moreover, rs3824949 CC genotype carriers had a lower viral load than patients bearing rs3824949 GG/CG genotypes (4.0 vs. 4.6 log copies/mL; p = 0.049); however, none of the variants affected CD4⁺ cell count. In conclusion, our data confirm the role of TRIM5 variants in the HIV-1 transmission and the clinical course of HIV-1 infection. The presence of rs7127617 TT genotype and T allele seems to protect against HIV-1 transmission in examined population.