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

通过抗 HIV 抗体组合来预防 HIV 传播的粘膜保护

• 批准号: 7500822
• 负责人: Lisa A Cavacini
• 金额: $ 24.03万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500822
• 关键词: Animals; Antibodies; Area; Binding; Binding Sites; Biological Response Modifiers; CD4 Lymphocyte Count; Cell Line; Cells; Central Asia; Chinese Hamster Ovary Cell; Class; Condition; Country; Dendritic Cells; Eastern Europe; Environment; Epitopes; Family suidae; Female; Frequencies; Gel; HIV; HIV Antibodies; HIV-1; Human; Human Cell Line; Hybridomas; IgA1; IgA2; Immune response; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulin Variable Region; In Vitro; Incidence; Individual; Inequality; Infection; Infection prevention; Inflammation; Inflammatory Response; J-Chain Immunoglobulins; Light; Lymphocyte; Macaca; Measures; Mediating; Metabolic Clearance Rate; Methods; Modeling; Monoclonal Antibodies; Mucosal Immunity; Mucous Membrane; Numbers; Prevalence; Prevention; Prevention program; Proteins; Range; Resistance development; Role; Sex Behavior; Sexual Transmission; Simulate; Site; South Africa; Southeastern Asia; Structure; Structure-Activity Relationship; Surface; Sus scrofa; System; Tail; Testing; Time; Tissues; V3 Loop; Vagina; Variant; Viral; Viral Load result; Viral Physiology; Virus; Woman; antibody-dependent cell cytotoxicity; base; expression vector; functional outcomes; human monoclonal antibodies; improved; in vivo; in vivo Model; lymph nodes; male; microbicide; neutralizing antibody; nonhuman primate; physical property; polymeric IgA; portability; prevent; protective effect; prototype; simian human immunodeficiency virus; social; transcytosis; transmission process

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.

描述（由申请人提供）：2005年，全世界约有500万人新感染HIV-1，妇女感染率增加，特别是在非洲、南亚和东南亚、东欧和中亚，那里的社会和文化不平等严重影响妇女预防感染的能力。虽然预防方案可以成功地减少传播的发生率，假设他们是长期和密集的，许多人没有机会获得预防方案或不知道他们的伴侣的艾滋病毒状况。必须发展更多的预防手段，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，20%的妇女定期使用60%有效的杀微生物剂将防止数十万人感染。被动给予或局部应用人单克隆抗体已被证明可有效预防非人灵长类动物模型中的粘膜感染。我们假设，这些单克隆抗体的结构可以改变，以提高在粘膜表面配制的杀微生物剂，可以提供持久的，方便的，可靠的和局部有效的预防体内功效。为了研究这些假设，我们建议：（1）确定伊加亚类和单体或聚合物结构与抗HIV抗体的功能活性和粘膜环境中的稳定性的关系;和（2）确定预防非人灵长类动物阴道攻击后感染的功效。特异性抗体已经基于广泛的反应性、结构-功能关系、表位暴露和可用性被鉴定，并且包括：F425 A1 g8，与通过CD 4结合暴露的表位反应，具有中和活性; b12，与CD 4结合位点反应，中和广泛的分离株; F425 B4 e8，与V3环反应，中和广泛的分离株; F240与gp 41反应，与HIV的所有分支结合，当表达为伊加抗体时中和感染。F240代表一类抗体的原型，其可包括对充分保守的位点具有广泛反应性的其他抗体，所述位点可介导局部破坏或隔离病毒远离靶细胞，以通过粘膜表面上普遍存在的先天免疫介质进行破坏或在特定条件下中和感染。提出的研究探索了这样的假设，即在粘膜局部表达广泛抗HIV-1抗体的组合代表了阻止病毒进入体内的有效方法。