Role of T regulatory cells in pathogenesis of HIV-2 infection

Abstract

Infection with the HIV-2 virus can result in progression to acquired immunodeficiency syndrome (AIDS) similar to that seen in HIV-1 infections. However, the majority of HIV-2 infected individuals do not show evidence of disease progression and maintain a functional immune system. It was hypothesized that there was a better balance between effector and regulatory responses in HIV-2 infection that contributed to virus control and immune activation. Furthermore, the role of T regulatory cells was investigated in the development of Immune Reconstitution Syndrome in HIV-1 and HIV-2 patients commencing antiretroviral therapy. In the present study I first determined the appropriate immunological signature of Tregs in HIV infections. Tregs were defined on the basis of CD4+CD127lo/-FOXP3+ and were shown to be strongly correlated with CD4+CD25+FOXP3+ or CD4+FOXP3+ cells. However measurement of Tregs using flow cytometry and real time PCR did not correlate. Hence measurement of Tregs from whole blood using flow cytometry was used in subsequent studies. HIV-2 infected subjects had a significantly lower percentage and absolute number of Tregs compared to HIV-1 infected individuals when matched by CD4 count. In both infections, Treg percentage increased as CD4 T cell count declined while the absolute level was positively correlated with CD4 T cell count. In addition the percentage levels of Tregs positively correlated with the immune activation and viral load in HIV-2 infection only. The next study measured the level of HIV specific immune responses and immune activation in asymptomatic HIV-1 and HIV-2 patients. HIV-2 infected subjects showed much higher percentage levels of HIV specific CD4 and CD8 T cell and lower percentage levels of activated T cells. Furthermore, it was shown that Tregs in HIV-2 patients were functional as their depletion resulted in increased HIV specific immune responses from CD4 and CD8 T cells. To assess whether Tregs contributed to the development of Immune Reconstitution Inflammatory Syndrome, HIV-1 and HIV-2 infected patients that were scheduled to commence antiretroviral therapy were recruited and followed up for six months. Longitudinal measurement of Tregs showed no differences in the magnitude or trend of percentage or absolute numbers in patients that developed IRIS compared to those that did not. Collectively these results suggest that the balance between effector and regulatory responses is maintained in HIV-2 infections which may in turn contribute to the improved prognosis of these patients compared to HIV-1 infections. The IRIS study showed that Tregs did not influence the development of IRIS though further functional characterization of these cells is required.