Innate and adaptive antiviral immune mechanisms are crucial for the control of HIV-1 replication, although the virus has evolved mechanisms to thwart these processes [13
]. Host cells also possess intrinsic antiviral restriction factors that play an important role in host antiviral defense [17
hu is a host restriction factor with a largely unknown influence on HIV-1 restriction in vivo.
In the present study, we found that levels of TRIM5αhu expression were higher in HIV-1–negative individuals than in HIV-1–infected individuals. This result suggested 2 possibilities: either TRIM5αhu is disregulated subsequent to HIV-1 infection (by direct down-regulation, targeted killing of cells, or translocation of TRIM5αhu-enriched cells away from peripheral blood) or those who acquired HIV-1 infection had lower levels of TRIM5αhu at baseline. To discriminate between these possibilities, we used samples from a longitudinal follow-up cohort and compared TRIM5αhu mRNA levels in preinfection samples obtained from 13 individuals who subsequently became seropositive with similar samples obtained from 44 nonseroconverters who were in the same cohort. Interestingly, the data showed that nonseroconverters had significantly higher TRIM5αhu mRNA levels.
We acknowledge that the small size of the sample of seroconverters who had matched preinfection samples was a limitation of this study; therefore, this finding needs to be interpreted cautiously. However, we can be fairly confident about the findings for this cohort, because of the stringent criteria for determination of HIV infection status that were used in this study, which included 2 antibody tests and a confirmatory RNA PCR assay. Furthermore, analysis revealed that the postinfection TRIM5αhu mRNA levels of the 13 seroconverters did not significantly differ from those of other seroconverters for whom preinfection samples were unavailable; this finding suggests that these 13 individuals were not unique in having low TRIM5αhu levels by chance. If confirmed in other settings, the observation that low levels of TRIM5αhu are associated with a higher likelihood of HIV-1 acquisition has important implications for the role of TRIM5αhu as a mediator of relative resistance to HIV-1 infection. We can speculate that enhancing the expression of TRIM5αhu could be used as a novel strategy to protect against HIV-1 infection.
We also investigated whether HIV-1 infection is associated with disregulation of TRIM5α
hu expression. We showed that, in matched preinfection and postinfection samples, there was no significant difference in the median level of TRIM5α
hu expression. Median levels of TRIM5α
hu mRNA remained relatively steady throughout primary HIV-1 infection, although the levels did fluctuate from one time point to another within individuals. TRIM5α
hu has previously been shown to be an interferon (IFN)–α
–regulated gene [19
], and IFN-α
is transiently down-regulated during primary HIV-1 infection [20
]. We did not find a similar trend for TRIM5α
hu disregulation. We do not interpret this finding to suggest that TRIM5α
hu is not IFN-α
regulated, given strong previously reported evidence for this [19
]. Instead, we believe that this observation implies that there are complex transcriptional regulatory mechanisms for TRIM5α
in vivo, as has been recently suggested elsewhere [6
Previous studies show that another intrinsic antiviral factor, APOBEC3G, is down-regulated in HIV-1–infected PBMCs, compared with uninfected PBMCs [22
]. Our study extends these findings to another intrinsic antiviral factor. In addition, we analyzed matched HIV-1–infected and HIV-1–uninfected samples obtained from the same subjects, and we characterized the kinetics of expression during primary HIV-1 infection. Our data show that HIV-1 infection is not associated with down-regulation of TRIM5α
hu; rather, the expression of TRIM5α
hu is lower in high-risk individuals who develop HIV-1 infection. It will be important to investigate whether this finding can be extended to other intrinsic antiviral factors, such as APOBEC3G.
Finally, we reasoned that intrinsic antiviral factors are very likely to be involved as a first line of defense and that their effects might be more pronounced during primary HIV-1 infection. During the acute phase of infection, there was no significant correlation between TRIM5α
hu mRNA levels and plasma HIV-1 load, but there was a significant weak correlation with CD4+
T cell counts. In the early chronic phase of infection, we found no correlation between TRIM5α
hu mRNA levels and plasma viral loads or CD4+
T cell counts. We therefore conclude that TRIM5α
hu levels do not appear to contribute significantly to the rapid control of viral replication observed after peak viremia in acute infection, although the observation of a positive correlation of TRIM5α
hu mRNA levels with CD4+
T cell counts during the acute phase of infection is intriguing and may require further investigation in a larger sample size. Our results do not rule out the possibility of a long-term cumulative antiviral effect of TRIM5α
hu, as has been suggested by the recent identification of TRIM5α
capsid escape mutants [11
]; however, this can be addressed only with a larger, longer-term longitudinal cohort.
In conclusion, this first description of the expression of TRIM5α levels in association with HIV-1 pathogenesis in vivo has shown that TRIM5αhu mRNA levels are lower in PBMCs from HIV-1–positive subjects than in those from HIV-1–negative subjects. In addition, we have shown that these lower TRIM5α mRNA levels are most likely the result of seroconverters having significantly lower TRIM5αhu levels at baseline (before infection), compared with nonseroconverters. These results suggest that high TRIM5αhu levels could be protective against infection. Furthermore, our data suggest that HIV-1 infection is not associated with disregulation of TRIM5αhu at the transcriptional level. Finally, we found no negative correlation between TRIM5αhu levels and plasma HIV-1 load or consistent positive correlation with CD4+ T cell counts, and we conclude that TRIM5αhu levels have minimal or no effects on viral replication during primary infection. Further studies examining the contribution of TRIM5αhu to viral pathogenesis in different cell/tissue types, at different phases of infection, and in a wide variety of subjects are clearly needed. However, the results of this study suggest that the interaction between HIV-1 and TRIM5αhu may significantly affect the outcome of exposure to HIV-1 and that this interaction may therefore be an attractive target for the development of novel antiretroviral prophylactics.