Highly active antiretroviral therapy has dramatically reduced HIV-1 replication and viremia below the clinical limit of detection, and slows the rate of progression to AIDS. However, residual viral reservoirs still persist in a latent state in the formof integrated and transcriptionally silent proviruses, despite long-term antiretroviral therapy (ART), resulting in lifelong infection and viral rebounds in HIV-1-infected individuals upon ART cessation. The major obstacle to a cure for HIV infection is how to purge the persistently and latently HIV- infected cells in recessed tissues, especially in germinal centers (GC) of organized lymphoid tissues. With our novel-modulatory therapeutic strategy, we will reverse latently virus-infected cells, block replenishment of new reservoirs in GC, while simultaneously eliciting subdominant IgM responses in macaques on suppressive ART. To accomplish this we will sequentially administer ART, combined with the PKC activator prostratin (PRO) and immunomodulatory mTOR inhibitor rapamycin (RAPA) followed by anti-HIV-1 envelope antibody-drug conjugates (ADC) to eliminate residual infected cells. We hypothesize this comprehensive shock and kill strategy will also result in restoration of CTL function and improved antibody responses in infected hosts, which combined, may result in a sterilizing, or at least a functional cure for HIV in patients. The feasibility, safety, and efficacy of this cure strategy will be tested in the highly relevant SHIV model of HIV infection in rhesus macaques. Our long-term goal is to develop a sterilizing cure for HIV infected patients, and these studies will provide critical information as to the feasibility and practicality of this ambitious goal.
Novel strategies to cure HIV infection are desperately needed. Here we will sequentially investigate the effects of combinational antiretroviral therapy supplemented with a novel HIV latency reversing agent prostratin, in combination with the immunomodulatory drug rapamycin, on the reactivation and elimination of latently infected cells, blockade of reservoir replenishment, and elicitation of subdominant IgM and effective CTL responses in SHIV-infected macaques. Finally, we will test the ability of specific anti-HIV envelope antibody-drug conjugates to specifically eradicate any residual cellular reservoirs in tissues of animals on the combinational therapy. The efficacy of this novel, comprehensive, immunomodulatory therapeutic strategy to eliminate viral reservoirs and 'cure' pathogenic SHIV infection will be thoroughly tested in the highly relevant SHIV macaque model of HIV infection.
