In order to define better the dynamics and anatomical restrictions of Th17 cells during HIV infection, Brenchley et al. carried out a comprehensive analysis of Th17 cells from the blood, gastrointestinal (GI) tract and bronchoalveolar lavage (BAL) [65**
]. In this study, the authors first determined that Th17 cells are found in peripheral blood of healthy individuals, but these cells are comparatively enriched in the GI tract. The authors demonstrated that in both HIV-infected and uninfected individuals, Th17 cells respond to bacterial and fungal antigens such as Staphylococcus aureus, Streptococcal
kinase, Tetanus toxoid, and Candida albicans
, however Th17 cells were not specific for viral antigens, such as HIV, adenovirus, Cytomegalovirus (CMV), Epstein-Barr virus, and influenza. These data were further confirmed by Yue et al., who demonstrated that in uninfected and chronically HIV-infected individuals, IL-17 was not produced in response to either HIV or CMV antigens [70
]. Brenchley et al. went on to show that Th17 cells are preferentially lost from the GI tracts of chronically HIV-infected individuals as compared to uninfected individuals, but this loss of Th17 cells was not observed in BAL or peripheral blood, indicating that this phenomena is specific to the mucosal tissues of the GI tract. The authors furthered their analysis by demonstrating that CD4+ T cells in blood of HIV-infected patients are skewed toward a Th1 phenotype. In order to determine whether HIV preferentially infected Th17 cells, Brenchley et al. sorted IL-17+
, and IL-1−
cells from peripheral blood and determined the infection frequency of each subset using quantitative real-time PCR for HIV DNA. They found that Th17 cells were infected in vivo
, however there was no significant differences between the infection frequencies of any functional subset, suggesting that in peripheral blood Th17 cells are not preferentially infected. However, due to limitations with the number of cells available from GI tract biopsies, the infection frequency of Th17 cells in the GI tract was not determined. In order to ascertain if Th17 cells are lost in the GI tract after HIV infection due to direct virus infection or bystander effects such as inflammation and immune activation, further studies are required.
Interestingly, in this study the authors also determined the frequency of Th17 cells in the GI tracts of SIV-infected SM. Brenchley et al. found that there was no preferential loss of Th17 cells, which may suggest a possible mechanism by which SM maintain a healthy GI tract despite overall loss of GI tract CD4+ T cells. Further studies to determine whether Th17 cells are lost from the GI tracts of HIV-infected long-term non-progressors are needed to determine if this may be a mechanism of protection against microbial translocation and immune activation during non-progressive HIV infection.
Indeed, a study by Macal et al. demonstrated that some HIV-infected individuals that were given long term (>5 years) highly active antiretroviral therapy (HAART) were able to reconstitute both Th17 cells and overall frequencies of CD4+ T cells in the GI tract and periphery to healthy levels [71
]. In the individuals who received HAART and reconstituted CD4+ T cells, the levels of immune activation, as measured by gene expression levels, were decreased compared to HAART treated, HIV-infected, individuals who did not reconstitute CD4+ T cells. Instead, a low level of immune activation persisted in these individuals when compared to healthy controls. Thus the questions remain whether reconstitution of overall CD4+ T cells and Th17 in the GI tract translates into increased survival, and what happens to viremia after patients stop receiving HAART.