Ancient and Recent Adaptive Evolution in the AntiviralTRIM22Gene: Identification of a Single-Nucleotide Polymorphism That Impacts TRIM22 Function

Abstract

Tripartite motif protein 22 (TRIM22) is a novel interferon-induced protein that potently inhibits the replication of evolutionarily diverse viruses, including HIV-1. Altered TRIM22 expression is also associated with diseases, such as multiple sclerosis, cancer, and autoimmunity. The factors that influence TRIM22 expression and antiviral activity are largely unknown. In this study, we adopted an evolution-guided functional approach to identify potential genetic determinants of TRIM22 function. Evolutionary analysis of TRIM22 from mammals spanning >100 million years demonstrated that TRIM22 evolution has been shaped by ancient and variable positive selection. We showed that positive selection is operating on multiple TRIM22 residues that cluster in putative functional regions and that some are predicted to be functionally damaging. Interestingly, the second most prevalent TRIM22 SNP in humans (rs1063303) is located at one of these positively selected sites. We showed that the frequency of rs1063303:G>C varies up to 10-fold between ethnicities and that in some ethnicities SNP rs1063303:G>C is being actively maintained in the population. The SNP rs1063303:G>C variant also had an inverse functional impact where it increased TRIM22 expression and decreased the antiviral activity of TRIM22. Taken together, our data characterize the extensive genetic variation in TRIM22 and identify rs1063303:G>C as a highly prevalent SNP that influences its function.

Relationship of TRIM5 and TRIM22 polymorphisms with liver disease and HCV clearance after antiviral therapy in HIV/HCV coinfected patients

“…TRIM22 SNPs have been related to several aspects of viral infections such as HIV replication [30], chronic hepatitis B infection [31], and levels of specific antibodies and cytokines following measles and rubella vaccination [32, 33]. The TRIM22 rs1063303 G > C causes an arginine (R) to threonine (T) amino acid change at position 242 in the TRIM22 protein [43]. The TRIM22 rs1063303 GG variant correlated to an inverse functional impact where it increased TRIM22 expression and decreased the antiviral activity of TRIM22 [43].…”

“…The TRIM22 rs1063303 G > C causes an arginine (R) to threonine (T) amino acid change at position 242 in the TRIM22 protein [43]. The TRIM22 rs1063303 GG variant correlated to an inverse functional impact where it increased TRIM22 expression and decreased the antiviral activity of TRIM22 [43]. In this regard, the overexpression of TRIM22 negatively correlated with HCV viral load [25] and HIV-1 viral load [44], while gene silencing of TRIM22 enhanced HIV-1 infection of target cells [44].…”

Tripartite Motif 22 (TRIM22) protein restricts herpes simplex virus 1 by epigenetic silencing of viral immediate-early genes

“…For example, HIV-1 replication was higher in peripheral blood mononuclear cells (PBMCs) from human donors homozygous at SNPs rs7935564 G/G and rs1063303 G/G [31]. In contrast, the TRIM22 SNP rs1063303 C/C decreased TRIM22's antiviral function against HIV-1 [32]. Furthermore, the TRIM22 SNP rs10838543 C/C genotype in the Han-Chinese population is associated with chronic hepatitis B virus (HBV) infection [33].…”

“…The genetic variation in TRIM22-mediated inhibition of HSV-1 was defined by sequencing the TRIM22 gene locus in B lymphoblastoid cell lines (B LCLs) generated from the Caucasian and Yoruba cohorts [43] in the HapMap project [52]. These studies identified the following TRIM22 alleles in the populations studied encoding the following single nucleotide polymorphisms (SNPs) and the corresponding amino acid substitutions: rs7935564 A/G (N153D), rs1066303 G/C (R242T), rs61735273 C/T (S244L), rs73404240 C/A (T294K) [52] [31][32][33]39]. Therefore, to define the effect of the allelic variation on HSV-1 replication, we transfected HeLa cells with the vectors encoding the different TRIM22 haplotype forms [43] and infected the cells with HSV-1 7134 virus at a MOI of 0.…”

Intrinsic Cellular Defenses (TRIMS) in Modulating Viral Infection and Immunity

“…Interestingly, evolutionary analysis across different species clearly revealed that TRIM22 evolved under strong positive selection. Similar to TRIM5a, TRIM22 has been shown to interact with the HIV Gag protein, and since the majority of positive-selected amino acids are located within the PRY-SPRY domain, it is possible that this region is also important for TRIM22-Gag binding (Kelly et al, 2014;Hattlmann et al, 2012). Importantly, TRIM22 has also been shown to play a role in HIV-1 restriction in vivo.…”