Individualized HIV Curative Combination Strategy against Persistent HIV on ART - SUMMARY We have demonstrated multiple lines of evidence supporting the role for autologous neutralizing antibodies (anAbs) to restrict virus rebound. The positive relationship between anAb suppression of virus reactivation ex vivo and time to rebound in vivo indicates that anAbs are a strong host determinant in the suppression of the HIV viral reservoir. This offers a unique opportunity to develop an individualized HIV cure strategy targeting the anAb-resistant component of the HIV reservoir that is not controlled by the host upon reactivation. Taking advantage of the full complement of immune responses (i.e., a combination of innate, humoral and cell-mediated components), this proposal seeks to develop an individually tailored strategy that will bring together a) neutralizing antibody responses enhanced via mRNA-lipid nanoparticle (LNP) technology, b) anAb-resistant HIV Env HLA-E restricted adaptive NK cells or creation of multi-specific molecules targeting the HIV loaded HLA-E MHC complex, and c) engineered cell-mediated effector strategies, consisting of multivalent CAR T cells and CD64-transduced NK cells with a membrane-bound combinations of broadly neutralizing antibodies optimized against the anAb-resistant reservoir of each participant. Our preliminary data indicates that each of the strategies proposed has potential for antiviral control, supporting their inclusion in the combined approach proposed. Our central hypothesis is that characterization of the anAb-resistant HIV reservoir will permit development of a targeted, personalized combination strategy of antiviral innate, humoral and cell-mediated responses, which together will elicit sustained viral control and/or viral eradication. To test this hypothesis, we will first conduct comprehensive reservoir screens in persons with HIV suppressed on ART after early or late ART initiation (to evaluate strategies against distinct levels of reservoir diversity) to identify sequences of anAb-resistant reservoir viruses which will be used to generate individual tailored anAbs (induced by mRNA-LNP-based vaccination) and, concurrently, to identify the best combination of existing broadly neutralizing antibodies (bnAbs) that can achieve virus control. Second, we will build personalized cell-mediated responses to clear infected cells by (i) HLA-E responsive Env peptides for adaptive NK cell generation, (ii) phage display targeting for bi/tri-specific HLA-E- Env peptide complex engagers, and (iii) individually defined bnAb combinations loaded on to CD64-NK or expressed as tri-bnAb constructs on CAR T cells. To facilitate future clinical deployment of this combined immune strategy, we will develop personalized virus reactivation strategies, wherein individual’s CD4+ cells bearing integrated HIV will be characterized to design personalized LRA approaches optimized to maximize HIV reactivation. Together with significant institutional and industry commitment, our proposal brings together collaborative groups from Accelevir, Merck, Acuitas Therapeutics, BioNtech, BlueWhale Bio, CytoImmune Therapeutics, George Washington Univ., Univ. of Nebraska, Ragon Institute, Massachusetts Institute of Technology, Duke Univ., Philadelphia FIGHT Johns Hopkins Univ., Univ. of Pennsylvania, and Wistar Institute.
