IMPORTANCE OF ANTIBODY ISOTYPE IN VAGINAL HIV TRANSMISSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It is now clear that intestine and other mucosal tissues are of major importance in both the transmission as well as the early pathogenesis of HIV infection. We are currently determining whether antibodies of different isotypes are better for protecting the vaginal vault, and performed experiments to determine if there was preferential secretion. Last year we showed that HIV-specific IgA and IgG are preferentially secreted from the intestine (rectum) and vagina, respectively following intravenous administration of HIV-specific antibodies. Originally this was performed using antibodies against the membrane proximal external region (MPER) of HIV (2F5) but after receiving an administrative supplement to Dennis Burton at Scripps this year, we have also pursued this with other non-neutralizing antibodies (b12). However, we have not been able to demonstrate different levels of protection from vaginal transmission when any antibody to date in the IgA isotypes were used, and in fact IgG levels do seem to correlate better with protection. Whether this is a factor of not having the appropriate conformation (J-chain etc) of the IgA version of the same antibody is now being investigated. Further, we have other ongoing studies to determine whether the same effect occurs with different levels of neutralizing antibodies (2F5 vs b12). In CHAVI we have largely switched to examining MPER antibodies (2F5) as these are more conserved and apparently equally as effective in preventing transmission, especially when in IgG forms, and a paper is currently in preparation describing the distribution and efficacy of these antibodies in preventing vaginal SHIV transmission.