Here we showed that (i) all species of natural hosts we studied had significantly lower frequencies of CD4+ T cells than Asian macaques; (ii) AGM and patas monkeys had significantly elevated frequencies of CD4− CD8αdull T cells compared to rhesus macaques; (iii) all species of natural hosts had significantly higher frequencies of DN T cells than rhesus macaques; (iv) these high frequencies of DN T cells elicited effector functions normally attributed to CD4+ T cells; and (v) these DN T cells were less frequently infected by SIV than were memory CD4+ T cells. These data suggest that maintenance of immunological function among subsets of T cells resistant to SIV infection in vivo is an important mechanism underlying the nonprogressive nature of SIV infection that is common to multiple species of natural hosts of SIV.
While it is not entirely clear that such a mechanism could occur in humans, it is clear that these cells are only rarely infected by HIV in vivo
). Bolassel et al. recently showed that slow-progressing HIV-1-infected individuals have a significantly higher frequency of CD4−
T cells than chronically HIV-infected individuals (9
). This finding suggests that a phenomenon similar to what we have described here could slow disease progression in HIV-infected humans.
The ontogeny of the DN T cells, which are present at high frequencies and are capable of eliciting CD4-like effector function in the natural host species, is unclear. In humans and mice, the DN T cells are thought to be thymically derived and to negatively regulate other T cells in an antigen-specific fashion (reviewed in reference 27
). While we did not directly measure the regulatory function of this T cell subset, we clearly found expression of FoxP3 within the DN T cells. However, we also observed CD4-like functions within the DN T cells. Whether some of these cells originated from the CD4+
T cell pool, like the CD8αdull
T cells in AGM (4
), and maintained major histocompatibility complex class II restriction remains unclear, but further experimentation is clearly warranted. Indeed, recent data from humans have suggested that, under inflammatory conditions, DN T cells are fairly plastic and are capable of producing IL-17 (14
Some of the DN T cells in primates belong to the subset of NK T cells (10
). These T cells with rearranged, but invariant, T cell receptors respond quickly after infection and have evolved to recognize CD1d-presented lipid antigens. These cells are thought to play important roles during infection with bacterial, viral, protozoan, and fungal pathogens (10
). Indeed, DN T cells are expanded in AIDS patients with disseminated Mycobacterium avium
). Moreover, recent studies of sooty mangabeys have shown that the NK T cells can be divided into two subsets based upon expression of CD8α. CD8α NK T cells tend to have a more cytolytic function, while DN NK T cells tend to produce effector cytokines typically expressed by CD4+
T cells (24
Of all African NHPs we studied, the only animals other than AGM which appeared capable of CD4 downregulation were patas monkeys. Patas monkeys are widespread in sub-Saharan Africa, their habitat overlapping with that of AGM. While they are not a known natural host of SIV, cross-species transmission of SIVagm from sympatric AGM species has been reported to occur in the wild (7
). Moreover, recent studies have shown that patas monkeys manifest a nonprogressive infection when infected experimentally with SIVagm (1
). Indeed, one patas animal with very low numbers of CD4+
T cells appeared to be resistant to infection with SIVagm (1
). Hence, patas monkeys may have adapted similar mechanisms to avoid infection completely. Indeed, the patas animals had very high frequencies of DN T cells and maintained significantly high frequencies of cells capable of CD4-like functions. Whether some of these cells were originally CD4+
T cells that did not upregulate CD8α is unclear.
The potential biological relevance of the DN T cells in natural host species has been highlighted by recent studies which demonstrated that sooty mangabeys infected with CXCR4/CCR5 dual-tropic SIVsmm lost the vast majority of all CD4+
T cells in peripheral blood and tissues, yet these animals did not succumb to simian AIDS (19
). While these animals were massively depleted of CD4+
T cells, the DN T cells persisted (19
), and recent studies suggest that DN T cells in SIV-infected, CD4-depleted, sooty mangabeys may elicit functions generally attributed to CD4+
T cells (18
). Indeed, we have shown that DN T cells are present at high frequencies in many species of mangabeys, that these cells are capable of eliciting CD4-like functions, and that these cells are rarely infected by SIVsmm in vivo
. Hence, it is tempting to speculate that maintenance of immunological function by subsets of cells resistant to viral infection in vivo
is an important mechanism underlying the nonprogressive nature of natural SIV infection. Moreover, the tendency of African nonhuman primates to have lower numbers of CD4+
T cells in vivo
may help explain why these animals tend to have lower plasma viral loads than SIV-infected Asian macaques.
Natural hosts have coevolved with SIV to avoid disease progression, although the mechanisms by which this occurs may diverge, since most SM maintain healthy frequencies of CD4+ T cells. This coevolution may have occurred, in part, via the development of T cell subsets that maintain immunological functions without susceptibility to SIV infection. Once the mechanisms by which CD4 downregulation and DN T cell development are understood, interventions, such as gene therapy, aimed at mimicking this phenomenon could be developed for preventative and therapeutic trials.