A multi-biologic, AAV-deliverable HIV-1 functional cure

About This Grant

PROJECT SUMMARY Broadly neutralizing antibodies (bnAbs) and the antibody-like biologic eCD4-Ig (eCD4) can suppress established HIV-1 and SHIV infections when they are present at sufficient concentrations. BnAbs and eCD4 can be delivered passively or expressed from a recombinant adeno-associated virus (rAAV) vector. rAAV expression bypasses cost and compliance concerns associated with periodic antibody infusions, as well as side-effects associated with a life-time of use of conventional or long-acting antiretroviral therapy (ART). Moreover, unlike ART, long- term antibody-mediated control engages multiple effector arms of the immune system, potentially accelerating the rate of decay of the proviral reservoir. eCD4, a potency and half-life enhanced CD4-Ig fused to a coreceptor-mimetic sulfopeptide, has several advantages over bnAbs. It is exceptionally broad, neutralizing all 200-plus HIV-1 and SIV isolates assayed. rAAV-expressed eCD4 (rAAV-eCD4) can protect from multiple high-dose challenges of both SHIV and SIV. eCD4 can combine with non-neutralizing CD4-inducible antibodies common in the sera of infected persons to mediate very potent antibody-dependent cell-mediated cytotoxicity (ADCC). More recently, we have shown that more potent and bioavailable forms of eCD4, combined with the bnAb 10-1074, can fully suppress established SHIV infections in both infant and adult macaques. We are therefore close to robust functional cures in rhesus macaques. The current application seeks to bring us across the finish line and identify antibodies and eCD4-Ig variants that would best function in a human clinical trial. To do so, we will therefore in Aim 1 compare new eCD4 sulfopeptide variants, determine the Fc-domain that best limits anti-drug antibodies and enhances expression, and ensure in vivo that eCD4 poses no risk of immune interference. Aim 2 presumes that a bnAb partner of eCD4 will be useful in maintaining long term viral suppression and asks what class of antibodies works with eCD4 most effectively. Several properties are considered: their inherent bioavailablity, potency, and breadth, and how they complement eCD4 to limit potential viral escape. Aim 3 then seeks to improve the former properties by employing a novel system whereby human antibodies affinity mature in wild-type mice, starting with bnAbs modified with largely germline framework regions, and selecting in vivo those with greater potencies and longer half-lives. Aim 4 applies knowledge that we have accumulated from the previous decades and insights from the previous aims to establish and compare functional cures mediated by eCD4 paired with optimized forms of CD4-binding site bnAbs and V3-glycan antibodies. Collectively, these aims will directly inform human clinical trials designed to suppress established HIV-1 infections without ART.