The results of the present study provide direct evidence that polymorphisms in TRIM5
contribute to the variable resistance of Indian-origin rhesus monkeys to mucosal SIV infection in vivo
. Recent studies have shown that SIV infections initiated by high-dose intravenous inoculation of rhesus monkeys bearing restrictive TRIM5
alleles result in the attenuation of replication rather than an outright block of infection (18
). In the present study, the demonstration that TRIM5
can potently restrict infection following mucosal exposures to SIV in settings that more resemble the conditions of sexual transmission suggests that the viral restriction conferred by TRIM5
alleles may be inversely proportional to the number of virus variants to which the monkeys are exposed. It is likely that a large multiplicity of infection of SIV can override TRIM5
restriction. Thus, the effect of TRIM5
on viral restriction at mucosal surfaces may be more profound than that of TRIM5
restriction in intravenous infections due to the inefficiency of viral transmission at the genital tract. Furthermore, our retrospective analysis of a cohort of rhesus monkeys that was challenged with SIVsmE660 intrarectally showed that there was also a significant association between the expression of two restrictive TRIM5
alleles and protection against SIV acquisition via the rectal mucosa (19
). Therefore, the effect of TRIM5
alleles on the susceptibility to mucosal transmission of SIV is likely generalizable to all mucosal compartments in Indian-origin rhesus monkeys.
The variability in set-point viremia in rhesus monkeys in the same cohort suggests that TRIM5 is not the only host genetic factor that influences SIVsmE660 replication in Indian-origin rhesus monkeys. To rule out the possibility that specific MHC class I alleles contributed to the lower levels of viral replication, we evaluated all 18 monkeys in the present study for the presence of the Mamu-A*01, -B*08, and -B*17 alleles. These MHC class I alleles have been implicated in the control of SIV replication in Indian-origin rhesus monkeys. Interestingly, the TRIM5 homozygous permissive monkey (DBFX) that resisted infection after 12 mucosal SIV exposures expressed the Mamu-B*17 allele, an allele that has been associated with low levels of viral replication. This observation raises the possibility that MHC alleles and host adaptive immune responses may have played a role in aborting systemic infection following mucosal exposure to virus. However, since no mucosal specimens were obtained and no other monkeys in this study expressed the Mamu-A*01, -B*08, or -B*17 allele, it is not possible to draw any conclusions regarding the role of MHC class I alleles in the mucosal acquisition of SIV. It is also likely that additional host restriction elements other than TRIM5 also contribute to the control of SIV. These as yet unidentified host restriction factors may have also contributed to the ability of monkeys DBFX and T8023 to resist mucosal infection.
Thus far, only a modest association has been described between TRIM5
alleles and the susceptibility to HIV-1 acquisition and AIDS pathogenesis in humans. The lack of a clear association is likely due to limited polymorphisms in human TRIM5
and retroviral adaptations in the human population (9
). However, the present results suggest that genetic factors play a significant role in restricting the mucosal acquisition of HIV-1. Therefore, efforts to illuminate potential genetic determinants that may contribute to host resistance to HIV-1 infection in various cohorts of highly exposed, HIV-1-uninfected individuals should continue.
Although the majority of HIV-1 transmissions in men worldwide occur across the penile mucosa, the cellular events involved in viral acquisition at the portal of entry are not well defined. Despite multiple epidemiologic trials that have demonstrated a reduction in the rate of HIV-1 acquisition in heterosexual men conferred by circumcision (2
), the biologic basis for this protective effect remains unclear. An understanding of the early events associated with HIV-1 acquisition in the male genital tract has been hampered by the lack of a robust, physiologically relevant animal penile transmission model. The reason for the absence of this transmission model is that it has been technically difficult to reliably initiate infections via penile exposures in nonhuman primates (NHPs) (27
). By exploiting our recent understanding of the role of TRIM5
in the mucosal acquisition of SIV, we have made significant progress toward establishing a novel and robust NHP penile transmission model for AIDS mucosal pathogenesis and vaccine research. Our results show that selecting Indian-origin rhesus monkeys with particular TRIM5
alleles can eliminate host restriction elements to create a more favorable setting for SIV penile transmission in rhesus monkeys. Furthermore, we have shown that this transmission model recapitulates key virologic and immunologic features of mucosal HIV-1 infection, thus lending credibility to the use of this model for HIV-1 mucosal pathogenesis, vaccine, and microbicide research. The SIV-rhesus monkey penile infection model should yield relevant insights into the biology of viral entry and target cells for infection in penile mucosal transmission of HIV/SIV.
The present findings have implications for the design and interpretation of HIV-1 pathogenesis and vaccine efficacy studies. The effect of TRIM5 in restricting viral acquisition should be considered specifically in the selection of rhesus monkeys for vaccine and pathogenesis studies in which SIV mucosal acquisition is an endpoint. TRIM5 genotyping should eliminate some of the variability in mucosal infection that can confound the results of mucosal pathogenesis and vaccine studies. In addition, a penile SIV challenge model will also provide a physiologically relevant challenge route for preclinical testing of candidate HIV-1 vaccines and microbicides. TRIM5 genotyping of rhesus monkeys combined with the use of this physiologically relevant route of penile virus challenge as part of a standardized screening algorithm may be more useful for identifying intervention strategies for blocking HIV-1 acquisition in men than the preclinical animal challenge models that are currently available.