Novel TRIM5 isoforms expressed by Macaca nemestrina

The TRIM5 family of proteins contains a RING domain, one or two B boxes, and a coiled-coil domain. The TRIM5alpha isoform also encodes a C-terminal B30.2(SPRY) domain, differences within which define the breadth and potency of TRIM5alpha-mediated retroviral restriction. Because Macaca nemestrina animals are susceptible to some human immunodeficiency virus (HIV) isolates, we sought to determine if differences exist in the TRIM5 gene and transcripts of these animals. We identified a two-nucleotide deletion (Delta2) in the transcript at the 5' terminus of exon 7 in all M. nemestrina TRIM5 cDNA clones examined. This frameshift results in a truncated protein of 300 amino acids lacking the B30.2(SPRY) domain, which we have named TRIM5theta. This deletion is likely due to a single nucleotide polymorphism that alters the 3' splice site between intron 6 and exon 7. In some clones, a deletion of the entire 27-nucleotide exon 7 (Deltaexon7) resulted in the restoration of the TRIM5 open reading frame and the generation of another novel isoform, TRIM5eta. There are 18 amino acid differences between M. nemestrina TRIM5eta and Macaca mulatta TRIM5alpha, some of which are at or near locations previously shown to affect the breadth and potency of TRIM5alpha-mediated restriction. Infectivity assays performed on permissive CrFK cells stably transduced with TRIM5eta or TRIM5theta show that these isoforms are incapable of restricting either HIV type 1 (HIV-1) or simian immunodeficiency virus infection. The expression of TRIM5 alleles incapable of restricting HIV-1 infection may contribute to the previously reported increased susceptibility of M. nemestrina to HIV-1 infection in vivo.