Linking Antibody Cooperativity and Effector Cell Engagement

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ABSTRACT_Project 2 A key goal for HIV-1 vaccine design is the induction of broadly neutralizing responses. Although this goal has not been achieved, preclinical studies in non-human primates have identified several vaccine strategies that achieved some level of protection without inducing broadly neutralizing antibodies. These findings and emerging data from the field indicate that an achievable path forward is to leverage a polyclonal response comprised of multiple antibody responses that work together to eliminate virus replication. A critical gap in knowledge is the nature of vaccine-elicited polyclonal antibody responses that can achieve protection against infection within mucosal tissues in the non-human primates in order to translate into protection in human clinical trials. Moreover, there is a lack of information on how best to design polyclonal combinations of non- neutralizing and neutralizing antibodies to recruit Fc-Receptor bearing cells at the mucosal compartment to leverage different antibody combinations for improved protection. Our central hypothesis is that the composition of polyclonal Ab responses significantly impacts recruitment of monocytes and NK cells and their cooperation for Fc-mediated functions. To test our primary hypothesis, we will evaluate combinations of monoclonal antibody and polyclonal vaccine-induced plasma antibodies for their ability to more efficiently kill infected cells by examining antibody-dependent cellular mediated killing and/or phagocytosis of infected cells. We will define the transcriptomic profile of Fc-receptor bearing cells recruited by effective polyclonal preparations to understand the optimal FcR-bearing cells that should be recruited by effective vaccine-induced antibodies. These signatures will enable to understand how species-specific FcR and cellular diversity impact translation from rhesus macaques to humans. Lastly, we will determine differences in the interaction between FcR-bearing cells recruited by optimal mAb combinations for their ability to eliminate infected cells and secrete antiviral cytokines with limited pro-inflammatory profile. These questions will be addressed in the following Aims: Aim 1. Define contribution of IgG1, IgG3, and IgA for recognition of infected cells and virus particles. Aim 2. Identify the functional properties of effector cell subsets recruited by IgG1, IgG3, and polyclonal Ab combinations. Aim 3. Determine whether monocytes and NK cells are serially recruited to eliminate infected cells.