Date Published: June 13, 2018
Publisher: Public Library of Science
Author(s): Nicole E. Behrens, Anne Wertheimer, Stephen A. Klotz, Nafees Ahmad, M. Firoze Khan.
Several studies have shown an increased accumulation of terminally differentiated T cells during HIV infection, suggestive of exhaustion/senescence, causing dysregulation of T cell homeostasis and function and rapid HIV disease progression. We have investigated whether long-term antiretroviral therapy (ART), which controls viremia and restores CD4 T cell counts, is correlated with reduction in terminally differentiated T cells, improved ratios of naïve to memory and function of T cells in 100 virologically controlled HIV-infected patients. We show that while the median frequencies of terminally differentiated CD4+ and CD8+ T cells (CD28-, CD27-, CD57+ and CD28-CD57+), were higher in the virologically controlled HIV-infected patients’ cohort compared with uninfected individuals’ cohort, the frequencies of these cells significantly decreased with increasing CD4 T cell counts in HIV-infected patients. Although, the naïve CD4+ and CD8+ T cells were lower in HIV patients’ cohort than uninfected cohort, there was a significant increase in both naïve CD4+ and CD8+ T cells with increasing CD4 T cell counts in HIV-infected patients. The underlying mechanism behind this increased naïve CD4+ and CD8+ T cells in HIV-infected patients was due to an increase in recent thymic emigrants, CD4+CD31+, as compared to CD4+CD31-. The CD4+ T cells of HIV-infected patients produced cytokines, including IL-2, IL-10 and IFN-γ comparable to uninfected individuals. In conclusion, virologically controlled HIV-infected patients on long-term ART show a significant reduction in terminally differentiated T cells, suggestive of decreased exhaustion/senescence, and improvement in the ratios of naïve to memory and function of T cells.
Human immunodeficiency virus (HIV) infection increases the population of terminally differentiated T cells, termed as premature aging of T cells [1–3], and rapid HIV diseases progression in infected patients with uncontrolled viremia [1–3]. Several HIV-induced immunologic changes in T cells are also seen in uninfected elderly population, referred as immunosenescence [1, 3], which likely occurs due to continuous viral replication, extreme activation and exhaustion of CD8+ T cells [3–5]. These age-related changes may result in dysregulation of T cell function and homeostasis and diminish the breadth of immune response in HIV-infected older individuals, which may contribute to increased susceptibility to new infections, frequent recurrent infections, and poor response to vaccinations . While long-term antiretroviral therapy (ART) has reduced the viral loads and restored CD4 T cell counts in many HIV-infected patients, it is not clear whether there is improvement in terminal differentiation, homeostasis and functions of T cells.
Here we provide evidence for immunological reconstitution, including a reduction in terminally differentiated T cells, based on the frequencies of CD4+/CD8+ CD28-, CD27-, CD57+ and CD28-CD57+ T cells, an improvement in ratios of naïve to memory and function of T cells in HIV-infected patients with controlled viremia and restored CD4 T cell counts due to ART compared with increased frequencies of terminally differentiated T cells in previously studied untreated HIV-infected patients with uncontrolled viremia [1, 3]. More importantly, we saw a phenotypic shift from CD28-, CD27-, CD57+ and CD28-CD57+ to CD28+, CD27+, CD57- and CD28+CD57- T cells moving away from terminal differentiation [19, 20]. In addition, the increased naïve CD4+ T cells in our HIV-infected patients were due to CD4+CD31+ (RTE), and the CD4+ T cells showed improved functions by producing cytokines, including IL-2, IL-10 and IFN-γ. Taken together, these findings suggest that reduction in terminally differentiated T cells, an indication of reversal of exhaustion/senescence of T cells, and improvement in ratios of naïve to memory and function of T cells occurred in HIV-infected patients likely due to suppression of viremia and improvement of CD4 T cell counts due to long-term ART.