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An effective HIV vaccine will need to incorporate protective antibody responses. Which type of responses, neutralizing, effector function inducing, which epitopes specificities, which breadth and potency these responses need to have and how they can be elicited awaits however further definition. In the present proposal we aim to obtain mechanistic insights into the modes of action of neutralizing antibodies (Aim A), derive information on the functionality of the humoral immune response to HIV in eliciting effector functions (Aim B), and to define the influence of the V1V2 domain of gp120 in steering the neutralization response against HIV (Aim C). Our studies will be based on both, in vitro studies using well defined monoclonal antibodies and ex vivo studies, based on the characterization of the developing humoral immune response from acute to chronic HIV infection. With these studies we aim to unravel central aspects of the mechanisms underlying the antiviral activity of the humoral immune response in vivo, knowledge of which is key to vaccine design.Aim A: Within this aim we propose to explore several mechanistic features of the inhibitory processes of neutralizing moncolonal antibodies directed to diverse epitopes and polyclonal responses elicited during HIV infection in vivo. We will analyze the kinetics of the neutralization process in both cell-free and cell-cell virus transmission and determine whether or not neutralization is irreversible. Building upon our recent discovery that MPER antibodies 2F5 and 4E10 inactivate HIV irreversibly by inducing gp120 shedding, we will explore the relevance of gp120 shedding induction in the neutralization process of diverse antibodies. By assessing the effects of neutralizing antibodies on virus pre- and post attachment to target cells, and during cell-cell transmission, we aim to gain a complete picture on the functionality of neutralizing antibodies at these steps of the virus life cycle. We will further expand our studies on the stoichiometry of neutralization to explore whether antibodies need to occupy one or more of their potential binding sites on the trimeric spike in order to inhibit HIV entry, cause irreversible neutralization or induce shedding.Aim B: Within this research aim we propose to investigate the role of effector functions mediated by the humoral immune response. A particularly emphasis will be put towards studying the interaction of HIV with professional phagocytes (monocyte derived macrophages and neutrophils) to determine the efficacy by which antibodies against HIV trigger phagocytic clearing. We will further assess the effects of antibodies on infected cells by assessing their capacity to elicit ADCC, ADCVI and inactivate progeny virus.Aim C: Within Aim C we propose a series of studies to define the role of the V1V2 loop within gp120 in steering sensitivity to neutralization. Specifically we will aim to i) Dissect monoclonal antibody specificities and polyclonal antibody responses elicited during HIV infection that depend or are counteracted by the V1V2 domain, ii) Define the mode of epitope shielding employed by the V1V2 loop in regulating the neutralization response, iii) Investigate the intra-patient evolution of the V1V2 domain and neutralizing antibody responses side by side, iv) Obtain functional insights into the role of the V1V2 loop in the entry process. These studies will provide us with detailed information how the V1V2 evolves to counteract neutralizing antibody responses elicited in vivo, which antibody responses are affected and may further allow definition of potential strategies for directing vaccine elicited responses to overcome restriction by the V1V2 loop.