Immune Dysfunction in Aging and Controlled HIV Infection: Implications for Influenza Vaccine Responses

Abstract

Aging and controlled HIV infection profoundly affect the immune system, leading to dysfunctional responses to infection and vaccination. Vaccines are among the first lines of defense against infection, and the primary measure of immune response magnitude is the level of serum antibodies against vaccine antigens. Although B cells and antibodies are important metrics of vaccine effectiveness, these humoral responses represent only one aspect of the immune response. Myeloid cells initiate the immune response, while CD4+ T cells orchestrate and regulate it across immune and non-immune cells. Prior work has not investigated broader CD4+ T cell and myeloid cell responses that may underlie impaired vaccine responses in older adults. In this dissertation, I used a systems immunology approach to investigate B, CD4+ T, and myeloid cell responses to influenza vaccine antigens in older adults over 65 without HIV and in people with HIV (PWH) on anti-retroviral therapy with controlled viremia, compared with younger and older adults without HIV. In chapter 2, I show that aging alters the phenotypes of CD4+ T helper cell subsets and negatively affects vaccine-reactive CD4+ T cell responses. RNA sequencing data revealed profound differences in antiviral transcriptional programming in CD4+ T cells and myeloid cells between younger and older adults. In chapter 3, I found that people with controlled HIV have detectable antigen-reactive CD4+ T cells, but the frequencies of these cells do not increase with vaccination. Furthermore, CD4+ T cells from PWH exhibit metabolic dysfunction, potentially affecting effector T cell function and immune responses to vaccination. Overall, my work presented in this dissertation will contribute to the development and evaluation of future vaccine efforts for older adults and people living with HIV.