Lifelong treatment of HIV-1 infection with combination antiretroviral therapy (cART) does not adequately address the issue of viral persistence. Eradication strategies for HIV-1 are likely to require a multi-faceted approach to reduce the latent reservoir, with key components focusing upon both the disruption of viral latency and the enhancement of cytotoxic T lymphocyte (CTL) function to promote killing of infected cells. In order to successfully achieve these objectives, we must investigate agents that safely stimulate reactivation of the latent reservoir AND explore approaches to enhance HIV-specific adaptive immunity to augment CTL function. We propose that this may be accomplished with a single therapeutic modality that is devised appropriately. Certain adjuvants that possess immunostimulatory properties may trigger transient activation of viral transcription while simultaneously enhancing HIV-specific CTL function and, thus, may play an important role in such a vaccine. Poly-ICLC (Hiltonol, Oncovir), is a synthetic Poly I:C or dsRNA complex, that is recognized by multiple pattern recognition receptors including Toll-like receptor 3 (TLR3). We and others have described the multi-faceted immune enhancing potential of Poly-ICLC including potent activation of dendritic cells (DC) to prime Th-1 type adaptive immunity, and stimulation of natural killer (NK) cells. Furthermore, our preliminary studies demonstrate that in addition to its adjuvant properties, Poly ICLC possesses the capacity to disrupt HIV latency in vitro. This occurs, at least in part, due to its activation of DC with subsequent bystander effects on infected CD4+ T cells. Taken together, our findings suggest that Poly ICLC may simultaneously activate the latent reservoir, while improving the ability of the innate and adaptive immune system to recognize and kill these infected cells. Here, we propose a proof of concept clinical trial to determine the ability of Poly ICLC to activate the latent viral reservoir and safely enhance innate immunity when administered systemically to HIVinfected individuals. This randomized, placebo-controlled study will administer two doses of subcutaneous Poly ICLC to HIV-infected individuals whom are virologically suppressed on combination anti-retroviral therapy (cART). We hypothesize that Poly ICLC will transiently disrupt viral latency while safely augmenting innate immunity, including DC and NK cell function. Should this be the case, Poly ICLC may serve as an ideal adjuvant for use with therapeutic HIV vaccines to reduce the number of latently infected CD4+ T cells in treated HIV-1 infected individuals.
Though effective antiretroviral medications have dramatically improved the survival of HIV+ subjects, this therapy remains limited because it fails to completely eradicate the virus. Persistent levels of virus, even at very low levels, create havoc on the immune system ultimately causing substantial health problems in the long term. This proposal will study the use of a vaccine adjuvant designed to increase the bodys immune defenses such that residual viral burden and its attendant health complications may be substantially reduced.
