Heroin use is associated with increased incidence of infectious diseases such as HIV-1 infection, as a result of immunosuppression to a certain extent. Host restriction factors are recently identified cellular proteins with potent antiviral activities. Whether heroin use impacts on the in vivo expression of restriction factors that result in facilitating HIV-1 replication is poorly understood. Here we recruited 432 intravenous drug users (IDUs) and 164 non-IDUs at high-risk behaviors. Based on serological tests, significantly higher prevalence of HIV-1 infection was observed among IDUs compared with non-IDUs. We included those IDUs and non-IDUs without HIV-1 infection, and found IDUs had significantly lower levels of TRIM5α, TRIM22, APOBEC3G, and IFN-α, -β expression than did non-IDUs. We also directly examined plasma viral load in HIV-1 mono-infected IDUs and non-IDUs and found HIV-1 mono-infected IDUs had significantly higher plasma viral load than did non-IDUs. Moreover, intrinsically positive correlation between type I interferon and TRIM5α or TRIM22 was observed, however, which was dysregulated following heroin use. Collectively, heroin use benefits HIV-1 replication that may be partly due to suppression of host restriction factors and type I interferon expression.

The origin of novel genes and their evolutionary fates are long-standing questions in evolutionary biology. These questions become more complicated for genes conserved across various lineages, such as TRIM5, an antiretroviral restriction factor and a retrovirus capsid sensor in immune signaling. TRIM5 has been subjected to numerous pathogenic challenges and undergone dynamic evolution, making it an excellent example for studying gene diversification. Previous studies among several species showed that TRIM5 gained genetic and functional novelty in a lineage-specific manner, either through gene duplication or a cyclophilin A retrotransposing into the TRIM5 locus, creating the gene fusion known as TRIM5-Cyclophilin A (TRIMCyp). To date, the general pattern of TRIM5 across the mammalian lineage remains elusive. In this study, we surveyed 36 mammalian genomes to verify a potentially novel TRIM5 pattern that uniquely seems to have occurred in tree shrews (Tupaia belangeri), and found that both gene duplication and retrotransposition worked jointly to form a specific TRIM5/TRIMCyp cluster not found among other mammals. Evolutionary analyses showed that tree shrew TRIMCyp (tsTRIMCyp) originated independently in comparison with previously reported TRIMCyps and underwent strong positive selection, whereas no signal of positive selection was detected for other tree shrew TRIM5 (tsTRIM5) genes. Functional assay results suggest a functional divergence between tsTRIMCyp and its closest paralog TRIM5-4, likely reflecting different fates under diverse evolutionary forces. These findings present a rare example of novel gene origination resulting from a combination of gene duplication, retrotransposition, and exon shuffling processes, providing a new paradigm to study genetic innovations and evolutionary fates of duplicated genes.

TRIM5α is a retroviral restriction factor, in which the B30.2 (SPRY) and coiled-coil domains cooperate to determine the specificity of TRIM5α-mediated capture of retroviral capsids. Here, all exons of TRIM5α were analyzed in 39 Vietnamese cynomolgus macaques (VCE) and 29 Chinese rhesus macaques (CR). Our results revealed the presence of 22 alleles using the PHASE 2.0 software package (PHylogenetics And Sequence Evolution), including two novel species-specific alleles with a low frequency in VCE in exons 4 and 8, which encoded the coiled-coil and B30.2 (SPRY) domains, respectively. Nine alleles were detected in both VCE and CR, while four alleles were likely shared between the species. Of these alleles, the highest frequencies of 38% and 26% occurred in VCE and CR, respectively. Importantly, we found that some alleles encoded the same coiled-coil domain, but not the SPRY domain. In contrast, other alleles encoded the same SPRY domain, but not the coiled-coil domain. Our findings will contribute to the understanding of the interaction between the two domains and the determination of the specificity of TRIM5α-mediated capture of retroviral capsids. Our results from the phylogenetic trees constructed for VCE and CR suggested that the macaques\' ability to inhibit SIV replication became gradually stronger if they carried corresponding alleles in four clades (clades4-7). More interesting, in clade3, both novel allele pairs (4E100a, 10E147a) and allele pairs (7R17b and 13R11b), which had the strong ability to inhibit SIV replication, originated from the same ancestral allele, suggesting that the novel alleles might play a key role to determine an animal\'s ability to inhibit SIV/HIV replication. However, further studies are needed to increase our understanding of the genetic background of TRIM5α in these two macaque species.