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

说明(申请人提供)：2005年，全世界约有500万新感染艾滋病毒-1病毒的人，妇女感染率有所增加，特别是在非洲、南亚和东南亚、东欧和中亚，这些地区的社会和文化不平等严重影响妇女预防感染的能力。虽然预防计划可以成功地减少传播的发生率，假设这些计划是长期和密集的，但许多人无法获得预防计划，或者不知道他们伴侣的艾滋病毒状况。必须开发更多的预防手段，以减少艾滋病毒的性传播。杀微生物剂可能是女性使用的一种有效手段。据估计，在受影响严重的国家，经常使用一种60%有效的杀微生物剂，由20%的妇女使用，可以预防数十万人的感染。在非人类灵长类动物模型中，被动给药或局部应用人类单抗已被证明在预防粘膜感染方面有效。我们推测，这些单抗的结构可以被改变，以提高作为杀微生物剂的粘膜表面的活体效果，从而提供持久、方便、可靠和局部有效的预防。为了研究这些假说，我们建议：(1)确定IgA亚类和单体或聚合物结构与抗HIV抗体在粘膜环境中的功能活性和稳定性的关系；(2)确定在预防非人灵长类动物阴道攻击后感染的有效性。根据广泛的反应性、结构功能关系、表位暴露和可用性已确定的特异性抗体包括：F425A1g8，与CD4结合的表位反应并具有中和活性；B12，与CD4结合部位反应，并中和广泛的分离物；F425B4e8，与V3环反应，并中和广泛的分离物；以及F240，与gp41反应，与HIV的所有分支结合，并在表达为IgA抗体时中和感染。F240代表了一类抗体的原型，该抗体可能包括针对保守部位的其他广泛反应的抗体，这些抗体可能介导病毒的局部破坏或隔离，使其远离靶细胞，以便由粘膜表面普遍存在的天然免疫介质破坏，或在特定条件下中和感染。这些研究提出了一种假设，即在粘膜上局部表达广泛的抗HIV-1抗体代表着阻止病毒进入人体的有效方法。

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.