(PTM) has become increasingly used as an invaluable model for AIDS virus pathogenesis studies; however, the characteristics of SIV infection in this Asian primate have not been comprehensively defined. Here, we evaluated the dynamics of SIVmac239 infection in PTM prior to infection, during acute infection, and throughout chronic infection until animals succumbed to simian AIDS. We found that in comparison to RM, PTM progress more rapidly to AIDS-defining illnesses after SIVmac239 infection, but this accelerated rate of disease progression was not attributed to increased peak or set-point plasma viral loads. This is of interest, as previous studies have demonstrated that SHIV, HIV-1, and HIV-2 replicate at extremely high levels in pigtail macaques (3
), and SIVagm replicates at variable levels (20
). However, somewhat lower SIVmac239 replication rates followed by progression to AIDS are consistent with the immunodeficiency that is observed in PTM after infection with SIVsun or SIVhoest, where animals progress to AIDS despite low levels of viremia (4
). Taken together, however, these data indicate that levels of peak and set-point viremia by themselves do not dictate the rate of progression to AIDS in PTM and that a variety of virological and immunological factors likely contribute to levels of acute and set-point viremia.
Similar to that observed in humans and RM, CD4+
T cell depletion in peripheral blood occurs in PTM after SIV infection, albeit at a more rapid pace, consistent with the observed rapid progression to AIDS. Also similar to SIV infection in RM and HIV infection in humans, massive depletion specifically occurred in memory/effector CD4+
T cell and CCR5+
T cell subsets, an observation which is consistent with the CCR5 tropism of SIVmac239 (13
). In contrast to HIV-uninfected humans and SIV-uninfected RM, we found that SIV-uninfected PTM had high levels of proliferation and turnover in the memory/effector T cell compartments.
Three of the nine PTM studied displayed an LTNP-like phenotype, all of which expressed Mane-A1*084. These animals maintained lower viral loads and higher levels of CD4+
T cells and at time of scheduled euthanasia (non-AIDS related) had survived nearly twice as long as the other 6 progressing PTM (P
= 0.0238). However, at time of euthanasia, CD4+
T cells in LTNPs started to be depleted, and thus, these animals may have eventually progressed to AIDS. This phenomenon has also been observed in HIV-infected elite controllers, where these individuals lose CD4+
T cells and have higher immune activation levels than HIV-uninfected individuals, despite low levels of viremia (22
). Thus, SIVmac239 infection in LTNP-like Mane-A1*084+
PTM may be valuable as a model for studying HIV-infected elite controllers.
It is of interest that while PTM have higher preinfection levels of immune activation than RM, the levels of T cell proliferation after SIV infection are similar to those observed in RM, and levels of T cell turnover actually tend to be lower than those observed in RM (50
). A previous report by Mason et al. (39
) suggested that preinfection levels of central memory T cells correlated with increased disease progression rates in PTM. However, we expand on that finding here, demonstrating that the overall rapid turnover and proliferation in T cell subsets in PTM regardless of infection status likely contribute to disease progression. Furthermore, we have previously reported (30
) that prior to SIV infection in PTM, there is increased damage to the gastrointestinal tract, microbial translocation, and immune activation compared to that observed prior to infection in RM, all of which may contribute to the increased mortality observed here. However, why this increased activation and turnover exist and precisely how this may contribute to rapid SIV progression in PTM should be more thoroughly investigated, including the study of mucosal immunity during SIV infection in PTM.
Overall, the dynamics of SIVmac239 infection in PTM are similar to the dynamics of HIV infection in humans and SIV infection in RM. However, this model provides many benefits as an alternate to using RM. First, the increased disease progression rate can be an asset when testing vaccination strategies and/or therapeutic interventions, as it will shorten the length of follow-up time during studies, thus expediting results and fraying expensive cage charges. Second, as discussed above, PTM tend to be larger and more receptive and cooperative to therapeutic strategies, thus making them ideal in large-scale, intensive sampling studies. Third, these animals are susceptible to a greater breadth of chimeric SIV and even HIV strains. Finally, the increased immune activation in PTM prior to SIV infection may better capitulate overall HIV infection, as the majority of HIV infections occur in developing countries, such as Africa, where individuals tend to have higher baseline levels of immune activation than individuals in developed countries (9
). Thus, taken together, PTM are an excellent model for HIV/AIDS pathogenesis, vaccine, and therapeutic studies, and the evaluation of SIVmac239 infection in PTM we describe here provides a standard for characterizing infection and disease progression in this model.