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Abstract
Human immunodeficiency virus type-1 (HIV-1) is the etiologic agent of acquired immune deficiency syndrome. Currently, there is no available efficacious HIV-1 vaccine. Most successful vaccines were developed by mimicking the protective immunity acquired during natural infections. However, the immune responses in HIV-1 natural infection cannot resolve HIV-1 infection. There are a series of immunopathological consequences to HIV-1 infection, such as depletion of HIV-1 CD4 T cells, B cell hyperplasia, and an increased prevalence of autoreactive antibodies (auto-Abs).
HIV-1 primarily infects and depletes CD4 T cells, including T follicular helper cells (TFH) and T follicular regulatory cells (TFR ), which are key cell populations in the generation of humoral immune responses in the germinal centers. Interaction of these cell populations along with antigen within germinal centers is a process known as GC reaction (GCR). The highly regulated GCR is essential for producing antigen specific antibodies, as well as restricting auto-Abs production.
We studied the frequency of B cells, TFH, and TFR cells and their association with auto-Abs during HIV-1 infection using the rhesus macaque (RMs) simian immunodeficiency virus (SIV) model. The T FH/TFR ratio increased significantly upon SIV chronic infection, which positively correlated with the levels of auto-Abs, suggesting that the TFH/TFR ratio plays a critical role in regulating antibody production during SIV infection. Therefore, we reasoned that modulating the TFH/TFR ratio through an immune adjuvant may help facilitate protective antibody responses by an HIV-1 vaccine.
Since Interleukin-21 (IL-21) is a critical cytokine that can enhance TFH cell differentiation and inhibit TFR function, we tested the effects of IL-21 as a molecular adjuvant on the humoral immune response in vaccinated mice. We found IL-21 improved the quality of antigen-specific antibody responses elicited by DNA-MVA prime boost vaccination. Finally, we studied the immune responses elicited by RV144-like vaccine in hu-BLT mice and detected antigen-specific cellular immune responses following vaccination, indicating the hu-BLT mouse model has the potential to evaluate human vaccine candidates.
In summary, this dissertation has addressed important questions regarding the humoral immune response in HIV-1 infection and vaccination. Our findings provided new insights for HIV-1 vaccine development.
