Longitudinal changes in cd4+ and cd8+t cell phenotype and activation marker expression among cryptococcal meningitis patients initiating on anti retroviral therapy

Abstract

Introduction: Since the introduction of antiretroviral therapy (ART), the prognosis for HIV-1 patients has improved immensely with CD4+T cell recovery and viral suppression. Early initiation of ART has been associated with immune reconstitution, however without a clear understanding of its immunological effects on the CD4+T cell repertoire. The study aimed at determining longitudinal phenotypic changes in the T cell subsets following ART initiation in HIV associated cryptococcal meningitis (CM). We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+T cells in HIV-associated CM. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from HIV positive patients with CM at four time points following ART initiation through the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+T cells isolated from a pool of PBMC samples was done by flow cytometry using T cell surface marker monoclonal antibodies. Results: Significant increases in the both CD4 and CD8+T cell counts were noted after week 4. There was a variation in the expression of immunophenotypic markers over the time points delineating a reduction in immune activation (CD38+ ,HLA-DR+), exhaustion (PD-1), an equipoise in the central memory (CD27+,CD45R0+) and a subsequent reduction in the effector memory markers (CD45R0+ ,CD27- ). In comparison to the CD8+T cells, markers of central memory declined gradually with trivial increases in the effector memory markers. Immune exhaustion and activation markers remained elevated throughout the time points. Conclusion: The relative surge and decline in the expression of T cell surface markers outlines that the differentiation of CD4+ T cells varies during ART treatment in HIV associated CM. Declines in the effector memory subsets possibly explain the adaptive immune response to Cryptococcal infection. Conclusively, complete CD4+T cell recovery after ART is a process that typically requires many years. The CD8+T cell pool does not seem to be influenced by the homeostatic forces associated with CD4+T cell depletion.