Determination of HIV-1 subtype may be important in the management of HIV infected individuals, particularly with regard to deciding the CD4 cell count at which to initiate ART. Non-B subtypes A and D are prevalent in Uganda and individuals infected with subtype D appear to have faster disease progression compared to those infected with subtype A. We examined the level of apoptosis in CD4+ T cells in a study cohort of volunteers infected with subtype A and D infection. Although the levels of apoptosis in the activated CD4+ cells significantly decreased with viral suppression, CD4+ apoptosis in individuals infected with subtype D were found to be significantly higher compared to those infected with subtype A prior to antiretroviral treatment. Surface expression of PD-1 on CD4 cells in subtype D was substantially higher compared to subtype A (p=0.03). This difference was not observed in the CD8 population (p>0.05). Our findings suggest that the infecting HIV subtypes exert an independent influence on the disease outcome in response to antiretroviral treatment.
Immune dysregulation in HIV-1 infection is associated with increased expression of inhibitory molecules such as CTLA-4, TGF-β, and IL-10. In this study we examined one potential mechanism for regulating TGF-β and IL-10 expression by HIV-specific suppressor CD8+ T cells. No overlap between TGF-β, IL-10, and IFN-γ cytokine production by HIV-specific CD8+ T cells was observed. TGF-β positive and IL-10 positive cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. TGF-β and IL-10 positive CD8+ T cells did not express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-β positive and IL-10 positive CD8+ T cell responses, and a concomitant increase in HIV-specific IFN-γ positive CD8+ T cell responses. Depletion of CD4+ T cells abrogated the impact of CTLA-4 on HIV-specific TGF-β positive and IL-10 positive CD8+ T cells. Our study suggests that CTLA-4 Signaling on CD4+ T cells regulates the inhibitory functions of the HIV-specific suppressor CD8+ T cells.
CD4þ T cell dysfunction in HIV-1 infection is associated with increased CTLA-4 and TGF-b expression. In this study we described a population of TGF-b-positive CD4 þ T cells with multiple HIV specificities. These HIVspecific TGF-b-positive CD4 þ T cells did not display the immunophenotypic patterns traditionally attributed to regulatory CD4 þ T cells. TGF-b-positive CD4 þ T cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. We also examined one potential mechanism for regulating TGF-b expression by HIV-specific CD4 þ T cells. Blocking of the TGF-b receptor II led to increased HIV-specific IFNg-positive CD4þ and CD8 þ T cell responses. Interestingly, HIV-specific TGF-b-positive CD4 þ T cells did not substantially express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-b-positive CD4 þ T cell responses, and a concomitant increase in HIV-specific IFN-g-positive CD4 þ T cell responses. Our study proposes a mechanism by which HIV-specific TGF-b production may be regulated by CTLA-4 engagement.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.