Improving Antibodies to Virion Based HIV Vaccines

改进基于病毒颗粒的 HIV 疫苗的抗体

• 批准号: 8391108
• 负责人: Kathie Grovit-Ferbas
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391108
• 关键词: AIDS/HIV problem; Adult; Animals; Antibodies; Antibody Formation; Antibody-mediated protection; Antigens; Area; Binding; Biological Assay; Caring; Cessation of life; Charge; Conflict (Psychology); Country; Data; Derivation procedure; Disease; Economics; Enhancing Antibodies; Enzyme-Linked Immunosorbent Assay; Epidemic; Epitopes; Exposure to; Failure; Formaldehyde; Funding; HIV; HIV Infections; HIV vaccine; HIV-1; Health Personnel; Heating; Hospitals; Human; Immune response; Immune system; Immunization; In Vitro; Infection; Life; Light; Link; Manuscripts; Medical center; Military Personnel; Mind; Mission; Monoclonal Antibodies; Mus; National Security; Persons; Physicians; Population; Preparation; Progress Reports; Prostitution; Proteins; Reagent; Refugees; Research Priority; Security; Soldier; Splenocyte; Structure; Testing; Time; United States; Vaccination; Vaccine Research; Vaccines; Veterans; Viral; Virion; Virus; base; fight against; immunogenic; improved; in vivo; neutralizing antibody; pandemic disease; pathogen; polyclonal antibody; public health relevance; sexual violence; tool; vaccine development

DESCRIPTION (provided by applicant): Emerging pathogens such as human immunodeficiency virus type 1 (HIV-1) are of central importance to VA Medical Centers across the United States. In fact, the VA is the single largest healthcare provider for adults infected with HIV in this country. Although it has been over 25 years since HIV-1 was first isolated, the virus remains an emerging pathogen worldwide with an average of 6,800 new infections, and 5,700 deaths occurring daily. Historically, vaccination has proven to be one of the most effective tools in the control of viral pandemics. Vaccine development is traditionally driven by naturally occurring protective immune responses. Unfortunately, this strategy has not proven to be successful in the fight against HIV. Moreover, the precise correlates of protection from HIV disease remain elusive. This has recently led to a redirection of the HIV vaccine research priorities. One of the critical areas identified in this effort is to "determine why broadly neutralizing antibodies (nAbs) are uncommon and how they can be elicited." The central hypothesis of this renewal application "Improving Antibody Responses to Virion Based HIV Vaccines" is that native HIV envelope (Env) is not an optimal antigen for the humoral immune system. As such, we believe that the failure of natural infection with HIV and of current vaccine strategies to induce protective antibodies (Abs) is linked to the inability of native Env to readily elicit these types of Abs. Thus it has become increasingly important to identify components of HIV Env that can induce protective antibody (Ab) responses, as well as to identify those components which may be involved in the elicitation of potentially detrimental enhancing antibodies. To this end, we have used Env modified formaldehyde and heat treated virions and pseudovirions as tools to study correlates of Ab mediated protection. During our initial funding period, we have isolated a panel of monoclonal antibodies (mAbs) immunized with Env modified heat treated virions. Interestingly, we have isolated mAbs which possess neutralizing activity and yet which fail to score positive in ELISA based binding assays against virions or HIV specific monomeric proteins. Overall the data presented here specifically demonstrate that Env modified heat treated virion based vaccines can show enhanced antigenicity in vitro and are immunogenic in vivo, and that unique mAbs can be isolated after immunization with these preparations. We hypothesize that these are precisely the types of reagents that can be successfully exploited to identify critical structures on Env that should be targeted and/or avoided in the eventual derivation of HIV vaccines.

描述（由申请人提供）： 诸如人类免疫缺陷病毒1型（HIV-1）之类的新兴病原体对美国的VA医疗中心至关重要。实际上，VA是该国感染了艾滋病毒的成年人的最大医疗保健提供者。尽管自HIV-1首次隔离以来已有25年以上，但该病毒仍然是全球新兴的病原体，平均有6,800种新感染，每天发生5,700例死亡。从历史上看，事实证明，疫苗接种是控制病毒大流行的最有效工具之一。传统上，疫苗开发是由天然发生的保护性免疫反应驱动的。不幸的是，这种策略尚未证明在与艾滋病毒的斗争中取得成功。此外，对艾滋病毒疾病的保护的精确相关性仍然难以捉摸。最近，这导致了HIV疫苗研究的重点重定向。这项工作中确定的关键领域之一是“确定为什么广泛中和抗体（NAB）并不常见，以及如何引起它们”。这种更新应用的中心假设是“改善对基于病毒素的HIV疫苗的抗体反应”是天然HIV包膜（ENV）不是体液免疫系统的最佳抗原。因此，我们认为，艾滋病毒和当前疫苗策略诱导保护性抗体（ABS）的自然感染失败与本地env无力容易引起这些类型的ABS有关。因此，确定可以诱导保护性抗体（AB）反应的HIV ENV的组成部分以及鉴定可能涉及可能有害增强抗体的那些成分的组成部分变得越来越重要。为此，我们使用了ENV修改的甲醛和热处理的病毒体和伪病毒作为研究AB介导的保护相关的工具。在最初的资金期间，我们分离了一组单克隆抗体（mAb），并用ENV修饰的热处理病毒体免疫。有趣的是，我们具有具有中和活性的孤立mAb，但在基于ELISA的结合测定中对病毒粒子或HIV特异性单体蛋白质的呈阳性。总体而言，此处提供的数据特别表明，ENV修饰的基于病毒体的疫苗可以在体外表现出增强的抗原性，并且在体内具有免疫原性，并且可以通过这些制剂进行免疫后分离出独特的MAB。我们假设这些恰恰是可以成功利用的试剂类型，以识别ENV上的关键结构，这些结构应在HIV疫苗的最终推导中被靶向和/或避免。