A human cytomegalovirus-based immunotherapy for HIV-1

DESCRIPTION The ultimate goal of this project is to develop an immunotherapy for human immunodeficiency virus HIV based on a spread deficient cytomegalovirus CMV derived vaccine expressing andquot tailoredandquot antigens designed for maximal coverage of clade B epitopes In non human primate models rhesus CMV vectored vaccines demonstrated unprecedented protection against highly virulent simian immunodeficiency virus SIV After initial infection SI was ultimately cleared from protected animals suggesting that CMV vectors can provide a therapeutic effect in infected individuals CMV vectors are unique in multiple aspects they can induce and maintain high levels of circulating and tissue resident effector memory T cells even when vectors are spread deficient in vivo Moreover in the absence of viral gene products that control T cell priming CMV vectors induce T cells to unconventional epitopes including MHC II restricted CD T cells Importantly CMV vectors can be used repeatedly and in CMV positive hosts without loss of immunogenicity HIV sequence diversity poses a challenge to HIV vaccine design However unlike prophylactic vaccines which strive to achieve the broadest possible coverage of HIV sub species therapeutic vaccines can be tailored towards the actual strains present in an infected individual In this proposal we will therefore test the hypothesis that a tailored vaccine cocktail selected from a small vaccine panel containing HIV antigens optimized for T cell epitope coverage of a given HIV clade are superior with respect to inducing andquot relevantandquot T cell responses as compared to non tailored approaches We will use novel algorithms to design tailored antigens that maximize epitope matches and we will insert these antigens into a new human CMV vector backbone developed at TomegaVax during phase I of this proposal We will monitor epitope specific T cell responses against specific HIV strains using a recently developed NHP model for HCMV Based on these results we will design our final vaccine cocktail To facilitate manufacturing of HCMV vectors under good manufacturing practices GMP we will generate a complementing master cell bank based on preliminary data showing for the first time HCMV growth in a cell type previously used for the manufacturing of unrelated viral vaccines Upon completion of this project we will have a designed characterized and developed a manufacturing strategy to generate clinical grade HCMV HIV vector products PUBLIC HEALTH RELEVANCE Currently the standard of care for HIV involves anti retroviral drug therapy for the life of the patient since these treatments are unable to clear latent reservoirs of HIV Recent work in animal models suggests that an HIV vaccine based on a novel cytomegalovirus vector not only limits the level of initial infection but ultimately clears virus e therefore propose development of an immunotherapy for HIV infected individuals using a version of human cytomegalovirus engineered to safely deliver antigens that are tailored to the HIV strains infecting an individual