ABSTRACT The persistence of the latent viral reservoir remains a hurdle for the cure of chronic HIV infection. Finding an effective and non-toxic means to purge and expose the viral reservoir has been elusive and is considered a major barrier to the cure. Because of their pivotal role in the initiation and regulation of adaptive T cell immunity, dendritic cells (DC) have been a therapeutic target for both cancer and HIV. Our most recent findings show that with optimal programming, DC have the provocative potential to both drive expansion of HIV-specific cytotoxic T cell lymphocytes (CTL), and to effectively induce HIV latency reversal (LR) to expose the infected cells for CTL targeting and elimination. We have determined that our specialized IL-12p70-producing type-1 polarized monocyte derived DC therapeutic platform (MDC1) can facilitate HIV LR when loaded with either CMV or HIV immunogenic peptides, suggesting that a considerable component of the HIV cellular reservoir is contained among CMV- and HIV specific CD4+ T cells. Here we propose the optimization of MDC1-based immunotherapy strategy that utilizes MHC class II associated CMV epitopes along with highly conserved MHC class I restricted HIV peptides as combined antigenic components designed to facilitate both the exposure of CD4+ T cells harboring latent HIV (the ‘kick’) and their elimination by HIV specific CTL (the ‘kill’). In our proposed studies we will dig deeper into the mechanisms involved, and we will translate our in vitro findings to test this approach in vivo using a humanized mouse model of HIV infection and MDC1 immunotherapy.