Influence of HIV and antiretroviral therapy on immunity to pneumococcal T-cell dependent antigens in Malawian adults

Abstract

Background: Natural immunity to S. pneumoniae is thought to rely on antigen-specific T and B memory that can be rapidly mobilised to mediate microbial clearance at the mucosal surface as well as interrupt multiplication following invasion. HIV infection however increases the risk of invasive pneumococcal disease (IPD) and pneumococcal colonisation, suggesting that natural-acquired pneumococcal immunity is compromised in HIV infection. The aim of this research project was to investigate the effect of underlying HIV infection on naturally-acquired pneumococcal immunity in Malawian adults and the impact of antiretroviral therapy on this immunity. Additionally, the study evaluated the effect of HIV infection on immune memory mounted in response to vaccine protein antigens. Methods: Peripheral blood mononuclear cells obtained from HIV-uninfected and infected Malawian adults were stimulated with pneumococcal concentrated culture supernatants derived from a standard strain D39 wild-type, isogenic mutant strain lacking pneumolysin (Ply-) and diphtheria toxoid. In vitro immune responses to these antigens were assessed by CFSE proliferation, T and B ELISpot, surface expression of CD 154 and cytokine production by intracellular cytokine staining and bio-plex cytokine assays. Additionally, the proportion of T and B cell subsets including naive, memory, senescent and regulatory cells were determined using flow cytometry. Results: Circulating central memory (T CM) and naive (T N) CD4+ T cells were preferentially lost in asymptomatic HIV infection. There was also an over representation of senescent and regulatory T cells in HIV-infected adults. Pneumococcal-specific immune responses were either compromised (IFN-γ effector responses, proliferative and CD 154 expression) or altered (IF -γ/IL-I0) in asymptomatic HIV infection. HIV infection also increased the prevalence of nasopharyngeal colonisation in adults with advanced disease. There was some regeneration of pneumococcal specific CD4+ T cell responses including effector memory responses, proliferative capacity, CD154 pathway and ability to produce simultaneously multiple cytokines following initiation of ART. However, there was no regeneration of antigen-specific memory B cell responses. T and memory B cell responses to protein vaccine antigen (diphtheria toxoid) were compromised and appeared short-lived in HIV-infected persons well-established on ART. Conclusion: The data from this research project showed that HIV infection compromises systemic naturally-acquired pneumococcal immunity and that there is some regeneration of this immunity following initiation of ART. It is not known however whether the re- constituted immunity is long-term and protective. The data also suggests that immune memory to vaccine protein antigens is compromised in HIV-infected adults and possibly short-lived even in individuals stable on ART. These findings have important implications for clinical care of HIV-infected persons on ART and future studies on pneumococcal immunity in the context of HIV infection and therapy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo