The reservoir of latently HIV-1-infected cells that persist during antiretroviral therapy is a critical barrier to curing an infected person. Strategies to purge this reservoir and prevent or control viral rebound include approaches to drive these cells into an activated state that causes viral replication, thereby rendering them susceptible to drugs and immune responses, which act by interrupting replication mechanisms and recognizing viral proteins respectively. It is likely that driving resting cellular immune responses or creating new ones via vaccination will be important to clear the resulting productively infected cells before they release enough virions to reseed the latent reservoir. Vaccines to generate such immunity are a key strategy in this overall “kick and kill” approach. In addition to driving anti-HIV-1 immunity, however, vaccines also cause immune activation of helper T lymphocytes, therefore potentially creating new targets for HIV-1 infection to add to the latent reservoir, and/or activating already latently-infected cells to become productive for HIV-1 replication. In this project, we investigate these component mechanisms with the specific aims: Aim 1: To evaluate the effect of vaccinations on reactivating the HIV-1 latent reservoir in CD4+ T lymphocytes. This will be explored using non-HIV-1 vaccines in humanized mice to generate pre-existing resting memory CD4+ T cell responses, followed by HIV-1 infection of the mice and treatment to generate a latent reservoir, and re-challenge with the same vaccines to drive activation of the resting memory cells. Aim 2: To evaluate the capacity of vaccinations to generate CD8+ T lymphocyte responses for clearing the reactivated HIV-1 latent reservoir. This will be explored using a novel protein nanoparticle HIV-1 vaccine that drives both CD4+ and CD8+ cellular immunity at high levels.