IMPORTANCE OF ANTIBODY ISOTYPE IN VAGINAL HIV TRANSMISSION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 现在很清楚，肠道和其他粘膜组织在HIV感染的传播和早期发病机制中都起着重要的作用。我们目前正在确定不同同种类型的抗体是否更有利于保护阴道穹隆，并进行实验以确定是否存在优先分泌。去年我们发现，静脉注射HIV特异性抗体后，HIV特异性IgA和IgG分别优先从肠道(直肠)和阴道分泌。最初这是使用针对HIV(2F5)膜近端外部区域(MPER)的抗体进行的，但在今年收到Scripps的Dennis Burton的行政补充后，我们也使用其他非中和抗体(B12)进行了这一研究。然而，到目前为止，当使用任何IgA同型抗体时，我们还不能证明对阴道传播的不同程度的保护，事实上，免疫球蛋白水平似乎确实与保护更好地相关。这是否是同一抗体的IgA版本没有适当构象(J链等)的一个因素目前正在调查中。此外，我们还有其他正在进行的研究，以确定不同水平的中和抗体(2F5与B12)是否会产生同样的效果。在CHAVI中，我们主要转向检测MPER抗体(2F5)，因为这些抗体更保守，显然在预防传播方面同样有效，特别是在免疫球蛋白形式时，目前正在准备一篇论文，描述这些抗体在防止经阴道传播SHIV方面的分布和有效性。

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.