IMPORTANCE OF ANTIBODY ISOTYPE IN VAGINAL HIV TRANSMISSION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 现在很清楚，肠和其他粘膜组织在HIV感染的传播和早期发病机制中具有重要意义。 我们目前正在确定不同同种型的抗体是否更好地保护阴道穹窿，并进行实验以确定是否存在优先分泌。 去年我们发现，HIV特异性伊加和IgG分别在静脉注射HIV特异性抗体后优先从肠道（直肠）和阴道分泌。 最初，这是使用针对HIV（2F 5）的膜近端外部区域（MPER）的抗体进行的，但在今年接受Scripps的Dennis Burton的管理补充后，我们也使用其他非中和抗体（b12）进行了这项研究。然而，当使用伊加同种型中的任何抗体时，我们还不能证明不同水平的阴道传播保护，事实上IgG水平似乎与保护更好地相关。 目前正在研究这是否是同一抗体的伊加版本不具有适当构象（J链等）的因素。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（2F 5 vs b12）是否会产生相同的效果。 在CHAVI中，我们主要转向检查MPER抗体（2F 5），因为这些抗体更保守，在预防传播方面显然同样有效，特别是在IgG形式时，目前正在准备一篇论文，描述这些抗体在预防阴道SHIV传播中的分布和功效。

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.