Therapeutic Conserved Elements (CE) DNA Vaccines in Simian-Human Immunodeficiency Virus (SHIV) or SIV-Infected Macaques

摘要

Antiretroviral therapy (ART) is highly effective at reducing viral replication, restoring CD4+ T-cells in the blood, and preventing AIDS in human immunodeficiency virus (HIV) infected people. However, ART cannot deplete the latent reservoir of dormant long-lived infected cells, thus requiring a lifetime of treatment. Lifelong ART has limitations including its high cost, potential side effects, and inability to fully reverse the inflammation and immune exhaustion induced by HIV-infection. These limitations have prompted the field to pursue immunotherapies and therapeutic vaccines the could provide durable viral control in the absence of ART, otherwise known as a "viral remission". A major barrier for a successful therapeutic HIV vaccine is the vast viral genetic diversity and the ability for the virus to mutate and "escape" effective immune responses with little or no loss of fitness. Encouragingly, broad HIV-specific T-cellular immune responses to conserved and functionally constrained epitopes have been associated with control of HIV in humans, and of simian immunodeficiency virus (SIV) in macaques. Vaccine immunogens have been designed that remove immunodominant variable portions of the viral proteome and consist exclusively of immunologically subdominant, conserved, and functionally constrained amino acid sequences. Towards this end, HIV/SIV conserved elements (CE) DNA vaccines have been developed and have demonstrated immunogenicity in SIV uninfected macaques. However, it was unknown if these responses could be induced in the immunodominant setting of viral infection and redirect T-cellular immune responses to CE sequences. I demonstrated that CE DNA vaccination induced broader cellular and humoral immunity to CE sequences in SHIV infected ART naive as well as SIV infected ART treated macaques. Furthermore, I demonstrated that T-cellular "exhaustion", or a limited functional capacity, prior to vaccination was inversely correlated with vaccine immunogenicity. Additionally, I identified that cellular exhaustion in the blood was correlated with SIV-induced perturbations in gut immune cell subsets and microbial translocation. In all, these findings demonstrate that CE DNA vaccines can overcome the canonical immunodominance hierarchies induced by viral infection, and that approaches to reverse cellular exhaustion (i.e. anti-PD-1 antibodies) and improve gut homeostasis may improve CE DNA vaccine immunogenicity.