The goal of therapeutic vaccination is to increase host immune control of HIV-1 to achieve durable virologic control in the absence of ART, which is defined as a “functional cure”. However, therapeutic vaccine studies in humans have to date been largely unsuccessful. We speculate that this may reflect the fact that prior vaccines (i) have failed to induce sufficient breadth of cellular immune responses and (ii) have not effectively activated or targeted the latent viral reservoir. We hypothesize that a therapeutic vaccine that induces potent and broad immune responses and that activates the latent viral reservoir will reduce the size of the replication- competent viral reservoir and will enhance virologic control following ART discontinuation. We have shown that Ad26/MVA therapeutic vaccination together with innate immune stimulation with a TLR7 agonist resulted in virologic control in a subset of SIV-infected rhesus monkeys following ART discontinuation. We therefore propose to evaluate the immunogenicity and efficacy of the Ad26/MVA + TLR7 agonist vaccine in HIV-1-infected humans to define its ability to control viral replication following discontinuation of ART. We also hypothesize that the addition of broadly neutralizing antibodies (bNAbs) may augment the antiviral efficacy of a therapeutic vaccine. To optimize both active and passive immunity, we propose a follow-up study to evaluate the optimal therapeutic vaccine together with bNAbs in HIV-1-infected humans. We therefore propose the following two Specific Aims: Specific Aim 1. To evaluate the safety, immunogenicity, and efficacy of Ad26/MVA therapeutic vaccination with TLR7 agonist administration in HIV-1-infected humans Specific Aim 2. To evaluate the safety, immunogenicity, and efficacy of Ad26/MVA therapeutic vaccination with broadly neutralizing antibodies (bNAbs) and a TLR7 agonist in HIV-1-infected humans

The latent viral reservoir represents the key barrier to cure HIV-1 infection. We propose the evaluation of a therapeutic Ad26/MVA vaccine with a TLR7 agonist and/or broadly neutralizing antibodies in ART-suppressed, HIV-1-infected humans. These regimens aim to induce potent and broad immune responses and to activate latent reservoir cells to render them susceptible to immune-based destruction.