HIV Immunotherapy: Host Immunity and Virus Evolution

Abstract

HIV-1 infection poses a major challenge to global public health. In spite of its huge clinical benefits, combined antiretroviral therapy fails to eradicate the virus from the body. Therefore, in the absence of a safe and effective preventive vaccine, HIV-specific cytotoxic T cell inducing therapeutic vaccination, aimed at limiting viral replication, presents a promising alternative strategy to contain the HIV-1 pandemic. The research described in this thesis studied the effects of HIV immunotherapy on the host immunity and on evolution of HIV. Dendritic cell (DC)-based immunotherapy against HIV-1 was evaluated in a clinical trial in which 17 HIV-1 infected patients were vaccinated with autologous DCs electroporated with mRNA of the HIV proteins Tat, Rev and Nef (DC-TRN) and subsequently interrupted antiretroviral treatment. We have demonstrated that DC-TRN is safe and induces in most patients HIV-specific T-cell responses. DC-TRN vaccination did not have a detectable impact on the virus sequence evolution in whole genes and CD8+ T-cell epitopes. However, it had a profound effect on the gene expression profile of the peripheral blood compartment. In order to optimize immunogen delivery, we have evaluated the immunogenicity of a replication-deficient recombinant influenza viral vector and an antigen-expressing immune-stimulatory liposomal non-viral vector. Both vectors were demonstrated to induce antibody formation and cytotoxic T cells. Our research has contributed to a better understanding of the immunogenic potential of viral vector systems and to the impact of a DC-based therapeutic vaccine on host immunity and virus evolution.