HIV infection of humans is associated with a predominant CD4+
T-cell loss at mucosal sites and chronic enteropathy.28,29
The gastrointestinal tract is continually exposed to food and bacterial antigens and the appropriate balance between regulatory and effector T-cell response maintains its integrity. Within the mouse, there is a complex interplay between inflammatory effector CD4+
T cells and regulatory CD4+
T cells. Transforming growth factor-β1 itself promotes the differentiation of CD4+
, which are involved in the control of autoimmunity.30
However, transforming growth factor-β1 together with IL-6 promotes the Th17 lineage31–33
by stimulating the expression of the required transcription factor retinoid-related orphan receptorγt.16
Furthermore, the addition of IL-6 inhibits the generation of CD4+
HIV-1 infects CD4+
reg in vitro34
T cells are depleted during SIV infection in the intestinal lamina propria.35
However, because phenotype markers such as CD25 and FoxP3 or gene expression profiles do not distinguish between activated and regulatory CD4+
T cells, the role of Treg
in HIV/SIV pathogenesis remains uncertain.36
Here, we demonstrate that in non-human primates the frequency of Th17 cells, but not Th1 cells, is significantly higher at mucosal sites than blood of healthy macaques and that infection with the pathogenic SIVmac251 differentially alters the balance between these two CD4+ effector subsets at mucosal sites. While in both acute and chronic SIV infection the number of both Th17 and Th1 cells is decreased in blood and lymph nodes, at mucosal sites only the frequency of Th17 cells is decreased during primary infection and it is not restored at normal level in the chronic phase of infection, except in animals able to contain viral replication.
The mechanism related to the apparent loss of Th17 cells remains unclear. We have provided evidence that SIVmac251 infects Th17 cells both in vitro and in vivo; however, the contribution of SIV infection to the apparent loss of Th17 cells needs to be ascertained. It is plausible that Th17 cells are highly activated in the gut because of continuous exposure to bacterial antigens and became a target for the virus.
Th17 cells produce IL-22, IL-17A, or IL-17F that together induce the expression of defensins and other antibacterial products.24
IL-22 also induces LPS-binding protein in hepatocytes37
and may prevent systemic inflammation provoked by LPS found in blood of HIV-infected individuals.27
The loss of Th17 cells may create a vicious cycle in SIV/HIV infection: decreased host defenses to bacteria may favor breaches of the gastrointestinal barrier and result in a further increase in local immune activation and exacerbation of viral replication in the gut. With time, increased local tissue damage could further favor bacterial translocation27
and systemic immune activation and lead to the progressive loss of all CD4+
T-cell subtypes from all compartments and development of AIDS.
An alternative hypothesis, however, is that there is increased recruitment of Th1 cells at sites of higher viral replication (the gut) with increased local production of INF-γ, a known inhibitor of Th17 differentiation.38
It will be of great importance to demonstrate whether there is a real loss of Th17 cells by examining intact tissues of naïve and infected macaques and to dissect the mechanism(s) underlining the decrease in frequency of Th17 cells, as this information could guide novel therapeutic approaches.
Bacterial infections are frequent in HIV infection. Recurrent bacterial infections are found in children infected with HIV and are associated with a faster decline of CD4+
HIV-infected individuals have an approximately 10-fold higher risk for bacterial pneumonia40
and diarrheal disease occurs with an odd ratio of 10 for AIDS.41
In developing countries, cryptococcal meningitis, cryptococcosis, and severe bacterial infection are considered AIDS-defining illnesses,42,43
and cryptococcal antigenemia has been well documented.44
Interestingly, the introduction of effective antiretroviral therapy has resulted in a decrease in cytomegalovirus-related hospitalization but bacterial infection predominantly increased in the following years.45 Candida albicans
induces Th17 polarization in vitro
and oral candidiasis and periodontal disease are frequent in untreated HIV-1-infected individuals.46
HIV patients also have increased susceptibility to Mycobacteria tuberculosis
. Interestingly, IL-23 and IL-17 may also be important in optimal responses to M. tuberculosis
Because of the potential roles of IL-17 in host defense against extracellular bacteria and fungi, it is tempting to speculate that the loss of Th17 cells likely plays a very important role in AIDS pathogenesis.
Our observation that macaques infected with SIVmac251 that do not progress to disease (elite controllers) have normal frequency of Th17 cells is in agreement with other groups (G. Silvestri et al., personal communication) who have found unchanged numbers of Th17 cells in the non-pathogenic SIV model in sooty mangabeys. Because SIV infection of sooty mangabeys results in high level of viral replication, but no disease, the maintenance of normal numbers of Th17 cells may be key in preventing disease development. The definition of the full spectrum of activity of Th17 cells will help to further our understanding of AIDS pathogenesis and hopefully guide new therapeutic approaches.