Though effective combination antiretroviral therapy (cART) has drastically reduced the morbidity and mortality associated with human immunodeficiency virus (HIV-1) infection, we must now focus on addressing the limitations of cART. Combination therapy for HIV-1 infection has not effectively overcome issues relating to viral persistence, which likely contribute to increased levels of immune activation. Chronic immune activation may limit immune reconstitution and predispose to non-immunologic complications of chronic infection. We propose to investigate whether an adjunctive immune based therapy can address these limitations. Specifically, we hypothesize that immunization with autologous dendritic cells (DC) pulsed with inactivated autologous virus ex vivo and administered with a potent adjuvant, Poly-ICLC, (polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose;Hiltonol(r), Oncovir), will stimulate innate and adaptive immune responses which will in turn reduce residual viral burden, decrease immune activation, and enhance virologic control when suppressive cART is interrupted. Through DC vaccination, we expect to bypass some of the mechanisms that HIV employs in vivo to compromise endogenous DC function and thus, impair effective formation of T cell responses. Furthermore, administration of a potent systemic adjuvant, Poly-ICLC (Hiltonol(r), Oncovir), should enhance vaccine immunogenicity by inducing the maturation, and consequently the immunogenicity of endogenous DC, allowing for efficient cross-presentation of injected DC-associated antigens. Successful DC immunization would provide valuable proof-of-concept that correction of defects in DC function in HIV-infected patients is vital to induction of adequate immune responses, paving the way for investigations of more practical immune based, DC-targeted therapies that may be applicable to a broader patient population.
The current treatment paradigm of lifelong antiviral therapy for HIV+ subjects with near perfect patient adherence to avoid the emergence of drug resistant HIV is associated with significant toxicity, failure to completely eliminate virus and substantial compromise of general health. By promoting virus-specific immunity through dendritic cell-based vaccination the goal is to stimulate innate and adaptive immune responses which will in turn reduce residual viral burden, decrease immune activation, and enhance virologic control so that cART can be successfully interrupted.
|Miller, Elizabeth; Spadaccia, Meredith; Sabado, Rachel et al. (2015) Autologous aldrithiol-2-inactivated HIV-1 combined with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose as a vaccine platform for therapeutic dendritic cell immunotherapy. Vaccine 33:388-95|