Protection from viral rebound after therapeutic vaccination with an adjuvanted DNA vaccine is associated with SIV-specific polyfunctional CD8 T cells in the blood and mesenteric lymph nodes

A therapeutic vaccine that induces lasting control of HIV infection has the potential to eliminate the need for lifelong adherence to antiretroviral therapy (ART). This study investigated the efficacy of a therapeutic DNA vaccine delivered with a novel combination of adjuvants and immunomodulators to augment T cell immunity in the blood and gut-associated lymphoid tissue. In SIV-infected rhesus macaques, a DNA vaccine delivered by intradermal electroporation and expressing SIV Env, Gag, and Pol, and a combination of adjuvant plasmids expressing the catalytic A1 subunit of E. coli heat labile enterotoxin (LTA1), IL-12, IL-33, retinaldehyde dehydrogenase 2 and the immunomodulators soluble PD-1 and soluble CD80, significantly enhanced the breadth and magnitude of Gag-specific IFN- γ T cell responses when compared to controls that were mock vaccinated or received the same DNA vaccine delivered by Gene Gun with a single adjuvant, the E. coli heat labile enterotoxin, LT. Notably, the DNA vaccine and adjuvant combination protected 3/5 animals from viral rebound, compared to only 1/4 mock vaccinated animals and 1/5 animals that received the DNA vaccine and LT. The lower viral burden among controllers during analytical treatment interruption significantly correlated with higher polyfunctional CD8+ T-cells (CD8+ T cells expressing 3 or more effector functions) in both mesenteric lymph nodes and blood measured during ART and analytical treatment interruption. Interestingly, controllers also had lower viral loads during acute infection and ART suggesting that inherent host-viral interactions induced prior to ART initiation likely influenced the response to therapeutic vaccination. These data indicate that gut mucosal immune responses combined with effective ART may play a key role in containing residual virus post-ART and highlight the need for therapeutic vaccines and adjuvants that can restore functional quality of peripheral and mucosal T cell responses before and during ART. Author Summary HIV has caused significant human disease and mortality since its emergence in the 1980s. Furthermore, although antiretroviral therapy (ART) effectively reduces viral replication, stopping ART leads to increased viral loads and disease progression in most HIV-infected people. A therapeutic vaccine could enable HIV-infected people to control their infection without ART, but none of the vaccines that were tested in clinical trials so far have induced long-lasting control of virus replication. Here, we used the SIV rhesus macaque model to test a therapeutic vaccine consisting of DNA expressing SIV proteins and a novel combination of adjuvants to boost virus-specific immune responses. We found that our vaccine strategy significantly enhanced SIV-specific T cell responses when compared to controls and protected 3/5 animals from viral rebound. We determined that lower levels of virus replication post-ART were associated with enhanced T cell immunity in the gut-draining lymph nodes and blood. Our study highlights the critical role of T cell immunity for control of SIV and HIV replication and demonstrates that a successful therapeutic vaccine for HIV will need to elicit potent T cell responses in both the blood and gut-associated tissues.