In the DNA prime, MVA boost model to be used in Project One of this applicafion, the only immune correlate of protection against mucosal challenge identified thus far is the GM-CSF mediated avidity of vaccine-elicited anfibody binding to the envelope ofthe challenge virus. The mechanism for protecfion is unknown but suggests an important role for the humoral immune response. The goals of the Virology and Anfibody Assay Core are therefore to investigate (i) a mechanism for GM-CSF-based antibody protection (Project One), (ii) novel strategies for promofing humoral immunity within the gut mucosa (Project Two), and (iii) vaccine and challenge induced anfibody specificities (NHP Monoclonal Anfibody Core). The Virology Core is central to these studies and will assess whether neutralizing and Fc-mediated anfibody acfivifies correlate with vaccine-induced protecfion. We will focus on antibodies within mucosal secretions and plasma against viral proteins Env and Gag. The neutralizing antibody component mediates antiviral activity by binding to the virion associated form of Env and preventing infection of a target cell. While neutralizing anfibodies are likely to be a critical component of a vaccine, to date no one has elicited Nabs that can mediate neutralizafion of genetically diverse viruses, a feature that is critical for protection of HlV-1 infected humans. Other nonneutralizing antibody acfivifies have been associated with protection against acquisifion and disease progression. These involve recognition ofthe Env expressed on the surface of an infected cell, leading to lysis of that cell (ADCC) in addition to augmenting other non-lytic mechanisms that may contribute to viral suppression (ADCVI). Finally, transmission of HIV-1 and SIV across the genital mucosa is associated with a genefic bottleneck, and we will therefore characterize the variants that establish infection in the vaccinated and control monkeys to determine whether vaccine-induced antibodies imposed selective pressure on Env. Specifically, the Virology Core will determine whether peripheral and mucosal IgG and IgA-mediated antibody activities correlate with immune protection against intravaginal challenge following vaccination and investigate whether a sieve effect is evident.
A successful vaccine against HlV-1 will likely need to elicit a B cell response that produces neutralizing and nonneutralizing anfibodies with activity against genetically diverse viruses. However, many questions must be answered to achieve this, including what kind of Env immunogen and delivery system is required to optimally elicit these types of antibodies with vaccination, are these anfibodies required at mucosal surfaces, and how do they limit acquisition or contribute to viral control? It is therefore important to fully characterize the B cell response and antibodies that are elicited in the mucosa and the periphery during pre-clinical vaccine studies and determine how they contribute to protection against intravaginal challenge. Ulfimately, it may be that multiple antibody-mediated activifies present in several compartments are needed to achieve the desired protection, and we will investigate that directly here.
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