Recent studies suggest that a massive depletion of CD4+
T cells occurs during acute infection, particularly in the GALT, where a substantial portion of the CD4+
T cells in the body reside (3
). As a result of frequent exposure to environmental antigens, the gastrointestinal mucosa is rich in recently activated cells and is thus an ideal site for viral replication. Massive viral replication may account for the extensive immune hyperactivation seen in the GALT during acute SIV and HIV-1 infection (21
), and there is a strong need to control the pool of activated target cells. A recent study by Mehandru et al. reported CD4+
T-cell hyperactivation in the GALT concomitant with the massive CD4+
T-cell depletion that is observed there during acute and early HIV-1 infection (23
). Given that Tregs suppress the activation and proliferation of effector lymphocytes, their decline during acute HIV/SIV infection would in turn reduce the active suppression of conventional T cells and, hence, contribute to immune hyperactivation.
The findings presented here provide strong evidence that SIV-mediated GALT depletion affects the distribution of Tregs in the GALT. Our data demonstrate a marked decrease in FoxP3 mRNA and protein levels by day 14 p.i., which we find to be concomitant to the loss of functional suppressive activity in the GALT of SIV-infected macaques. CD4+ T-cell destruction leads to the loss of critical regulatory functions and provides a continuous pool of activated T cells that maintain SIV replication. Tregs are not present to suppress the persistent inflammation resulting from continuous rounds of infection and activation of CD4+ T cells, thereby providing an optimal site for SIV pathogenesis and CD4+ T-cell depletion (Fig. ). Similarly, our mathematical simulations of CD4+ T-cell dynamics predict that the rapid loss of Tregs contributes to a dramatic decrease in the steady-state number of GALT CD4+ T cells in the setting of SIV infection due to the greater availability of activated target CD4+ T cells. Once a state of CD4+ T-cell hyperactivation has been achieved, there is an ensuing loss of effector cells, which ultimately manifests as increased susceptibility to opportunistic infections. Further work to examine the temporal relationship between gut-associated Treg depletion and activated CD4+ T-cell depletion is needed to confirm the causative role of Treg loss in CD4 depletion.
The depletion of Tregs observed here may occur as a consequence of the same pathogenic process that depletes CD4+
T cells from the GALT. Given evidence for the extensive infection of GALT CD4+
T cells during the acute phase (21
), it is possible that the Treg population in the GALT is depleted by direct viral cytopathic effects. We have shown that FoxP3+
Tregs from HIV-infected individuals are positive for HIV-1 DNA by real-time PCR (our unpublished data). In addition, FoxP3 has recently been shown to enhance gene expression from the HIV-1 long terminal repeat (13
), suggesting that infected Tregs may experience enhanced effects of HIV-1 gene transcription including the associated cytopathic effects.
Relocation to other anatomical sites could account for our observed loss of GALT Tregs. A recent study by Estes et al. showed an early increase in the frequency of Tregs in the LNs during acute SIV infection of rhesus macaques (7
). In addition, a study by Nilsson et al. showed that FOXP3 mRNA expression was increased in LNs from SIV progressors relative to SIV nonprogressors (24
). In our system, however, analysis of CD4+
T cells from the peripheral blood as well as mesenteric and inguinal lymph nodes showed similar FoxP3 expression levels in SIV-infected macaques compared to those in uninfected macaques, suggesting that relocation from the GALT to other sites either does not occur or is very transient. Even if Treg relocation is occurring, the repopulation of ileal Tregs did not take place during the time frame of our studies. We cannot rule out the possibility that the rapid depletion of Tregs observed here is unique to the SIV/pigtailed macaque model of HIV-1 disease used in our study. In this model, animals consistently develop AIDS within several months. In addition, we found that the percentage of CD4+
cells was high in the PBMCs of both uninfected and SIV-infected pigtailed macaques. Thus, an important caveat with studies using pigtailed macaques is that higher numbers of activated and proliferating cells could result in the acceleration of SIV infection and pathogenesis. A recent study of chronic HIV-1 infection by Epple et al. showed increases in duodenal Tregs that subsequently normalize after highly active antiretroviral therapy. That study suggests that Tregs are able to repopulate the gastrointestinal tract later in infection, when levels of viral replication are much lower than during the acute phase (6
In summary, we have shown that the GALT Treg population, crucial to controlling immune hyperactivation, is rapidly depleted in acute SIV infection. Mathematical simulations of CD4+ T-cell dynamics suggest that their loss contributes directly to ongoing CD4+ T-cell loss. Our findings underscore the need to implement therapeutic strategies designed to control immune hyperactivation early in acute HIV/SIV infection in order to limit GALT depletion of CD4+ T cells.