Mucosal Protection Against HIV Transmission by Combinations of Anti-HIV Antibodie

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DESCRIPTION (provided by applicant): There were approximately 5 million new infections with HIV-1 worldwide in 2005 with an increase in the prevalence of women becoming infected, especially in Africa, South and Southeast Asia, Eastern Europe and Central Asia where social and cultural inequalities significantly impact on a women's ability to prevent infection. While prevention programs can be successful at reducing the incidence of transmission assuming they are long-term and intensive, many individuals do not have access to prevention programs or are unaware of their partner's HIV status. Additional means of prevention must be developed to reduce the sexual transmission of HIV. A microbicide might be an effective means for women to use. It has been estimated that the regular use of a microbicide that is 60% efficacious by 20% of women in highly impacted countries would protect against hundreds of thousands of infections. Passive administration or local application of human monoclonal antibodies has been shown to be effective at preventing mucosal infection in non-human primate models. We hypothesize that the structure of these monoclonal antibodies can be altered to improve in vivo efficacy at mucosal surfaces formulated as a microbicide which can provide long-lasting, convenient, reliable and locally effective prevention. To study these hypotheses, we propose to: (1) determine the relationship of IgA subclass and monomeric or polymeric structure to functional activity of anti-HIV antibodies and stability in the mucosal environment; and (2) determine efficacy at preventing infection following vaginal challenge of non-human primates. Specific antibodies have been identified based on broad reactivity, structure-function relationships, epitope exposure and availability and include: F425A1g8, reactive with an epitope exposed by CD4 binding with neutralizing activity; b12, reactive with the CD4 binding site and neutralizes a broad range of isolates; F425B4e8, reactive with the V3 loop and neutralizes a broad range of isolates; and F240, reactive with gp41, binds to all clades of HIV and neutralizes infection when expressed as an IgA antibody. F240 represents a prototype of a class of antibodies that may include other broadly reactive antibodies to well conserved sites which may mediate local destruction or sequestration of virus away from target cells for destruction by innate immune mediators prevalent at the mucosal surface or neutralize infection under specific conditions. The studies proposed explore the hypothesis that local expression of a combination of broadly anti-HIV-1 antibodies at the mucosa represents an efficacious method to block entry of the virus into the body.