Background:  Rhesus macaque TRIM5a (rhTRIM5a), a potent HIV-1 inhibitor, reduces SIV infection, albeit less efficiently than HIV-1. Therefore, rhTRIM5a endogenously expressed in rhesus CD4⁺ T cells not only acts as a cross-species blocker for HIV-1, but also functions to regulate SIV infection.

Methods:  To investigate whether an intra-species polymorphism in the rhTRIM5 influences susceptibility to SIV infection, we analyzed cDNA of rhTRIM5a and rhTRIM5g, and determined the rhTRIM5 genotype of 8 rhesus macaques that exhibited distinct susceptibility to SIV infection in vitro and disease progression in vivo after SIV challenge:  4 of these exhibited high virus replication in vitro (high producer) and rapidly progressed to disease, and the other 4 animals showed low virus replication (low producers) and slow disease progression.

Results:  Compared to published rhTRIM5 sequences (referred to wild type, wt), we identified 2 distinct variant alleles:  1 variant allele in exon 8 contained 4 non-synonymous nucleotide changes and 6 bp in-frame deletion (called d6 allele). An rhTRIM5 haplotype bearing the d6 allele in exon 8 (d6-rhTRIM5) was predicted to affect the B30.2 domain of rhTRIM5a. Another variant allele (called dG allele) had extensive mutations in exon 4, intron 6, and exon 7, which were predicted to affect the coiled-coil domain of all rhTRIM5 isoforms. The dG allele occurred invariably on chromosomal haplotypes bearing the d6 allele. An rhTRIM5 haplotype carrying the both dG and d6 alleles (dG6-rhTRIM5) generated a non-functional rhTRIM5g mRNA encoding the C-terminal truncated protein and was found to be defective to generate rhTRIM5a mRNA. Thus, the dG6-rhTRIM5 haplotype was defective gene to produce a and g isoforms of rhTRIM5. In the low- and high-producers, we identified 4 rhTRIM5 genotypes (wt/wt, wt/d6, wt/dG6, and d6/dG6) constituting of the 3 haplotypes. Based on the rhTRIM5 genotypes, we predicted rhTRIM5a protein expression in the low and high producers:  of the 4 low-producers, 3 were predicted to express only wt-rhTRIM5a protein, whereas of the 4 high-producers, 3 were predicted to produce d6-rhTRIM5a protein (only d6- or both wt- and d6-rhTRIM5a).

Conclusions:  These results suggest that the polymorphism in rhTRIM5 resulting in a differential expression of wt- and d6-rhTrim5a might be an important host genetic factor determining the innate susceptibility to SIV infection and disease progression.

Keywords: TRIM5; SIV; polymorphism