ROLE OF NON-NEUTRALIZING ANTIBODIES IN PROTECTION FROM HIV

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。 在没有有效疫苗的情况下，必须寻求其他方法来防止人类免疫缺陷病毒1型(HIV-1)的性传播。为了指导疫苗设计，我们评估了针对HIV-1 gp120和f240上的免疫优势表位的人单抗b12和b6是否可以阻止SHIVSF162P4经阴道传播给猕猴。这两个抗gp120的单抗具有相似的单体gp120结合特性，但b12具有很强的中和性，而b6则不是。F240是非中和性的。强中和单抗B12经阴道大剂量应用后，对7只动物、0只B6动物和2只F240动物产生杀菌免疫。与对照动物相比，B12的保护作用达到统计学意义，而F240的保护作用不显著。另外的被动转移实验也表明，给予的抗gp120单抗中和挑战病毒的能力是保护的关键影响因素。此外，在接受单抗b6的动物中，与其他未受保护的猕猴相比，建立感染的创立者病毒的数量显著增加。因此，gp120结合的、非中和的抗gp120的单抗在保护方面充其量是完全无效的。Gp41的非中和抗体的保护能力可能有限，但结果表明，HIV-1疫苗研究的中心焦点应该是诱导病毒中和抗体。

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. In the absence of an effective vaccine, other methods for preventing the sexual transmission of human immunodeficiency virus type 1 (HIV-1) must be pursued. To guide vaccine design, we assessed whether human monoclonal antibodies (MAbs) b12 and b6 against the CD4 binding site on HIV-1 gp120 and F240 against an immundominant epitope on gp41 could prevent vaginal transmission of SHIVSF162P4 to macaques. The two anti-gp120 MAbs have similar monomeric gp120-binding properties, measured in vitro, but b12 is strongly neutralizing while b6 is not. F240 is non-neutralizing. Applied vaginally at a high dose, the strongly neutralizing MAb b12 provided sterilizing immunity in 7/7 animals, b6 in 0/5 animals and F240 in 2/5 animals. Compared to control animals, the protection by b12 achieved statistical significance whereas that due to F240 did not. Additional passive transfer experiments also indicated that the ability of the administered anti-gp120 MAbs to neutralize the challenge virus was a critical influence on protection. Furthermore, there was a significant increase in the number of founder viruses establishing infection in animals receiving MAb b6, compared to other non-protected macaques. Thus a gp120-binding, non-neutralizing MAb against gp120 was, at best, completely ineffective at protection. Non-neutralizing antibodies to gp41 may have a limited capacity to protect, but the results suggest that the central focus of HIV-1 vaccine research should be on the induction of virus-neutralizing antibodies.