GBV-C E2 protein mimics a cellular antigen involved in HIV-1 entry

GBV-C E2 蛋白模拟参与 HIV-1 进入的细胞抗原

• 批准号: 8330378
• 负责人: Jinhua XIANG
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330378
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Animal Model; Antibodies; Antigens; Antiviral Agents; Behavior Therapy; Behavioral Research; Binding; CD4 Positive T Lymphocytes; Caring; Cause of Death; Cell fusion; Cell membrane; Cell surface; Cells; Communicable Diseases; Data; Developing Countries; Development; Epidemic; Epidemiology; Epitopes; Escape Mutant; Future; Fuzeon; GB virus C; Generations; Glycoproteins; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV vaccine; HIV-1; Human; Human Virus; Immune response; Immunization; In Vitro; Individual; Infection; Life; Lymphocyte; Mediating; Medical; Membrane; Meta-Analysis; Methods; Mission; Modeling; Molecular Structure; Monkeys; Monoclonal Antibodies; Mumps; Mus; Oryctolagus cuniculus; Patients; Peptides; Pharmaceutical Preparations; Phospholipids; Play; Population; Proteins; RNA-Directed DNA Polymerase; Recombinants; Research; Research Design; Resistance; Retroviridae; Role; Structure; T-20; T-Lymphocyte; Tertiary Protein Structure; United States; Vaccines; Vesicular stomatitis Indiana virus; Veterans; Viral; Viral Load result; Viremia; Virus; Yellow fever virus; base; design; in vivo; insight; mortality; neutralizing antibody; novel; particle; tool; transmission process; vaccine development

DESCRIPTION (provided by applicant): Development of an HIV vaccine has proven difficult; although recent studies suggest that some protection against HIV is possible. Over the past 16 years, antibodies have been found in HIV-infected (and HIV-uninfected) humans that neutralize diverse isolates of HIV in vitro. Administration of a cocktail of these broadly neutralizing HIV antibodies decreased HIV viral load in infected humans and to reduced HIV transmission in a monkey model of HIV transmission. Extensive characterization of these HIV neutralizing antibodies has been conducted, and it is known that the some of these antibodies are polyspecific, recognizing a hidden region on the HIV glycoprotein that is involved in virus-cell fusion (gp41), and with cellular constituents that may also play a role in HIV entry. Thus far, the major limitation of thee antibodies is that they have not been able to be reproducibly or potently produced following immunization with either the HIV gp41 or with cellular components. I found that a common, apparently nonpathogenic human virus (GB virus C) inhibits HIV replication in vitro, and that HIV infected people who are coinfected with GBV-C live longer than those who do not have GBV-C. We found that GBV-C infects lymphocytes, including CD4 cells, and others found that the GBV-C envelope glycoprotein E2 inhibits HIV fusion, much like a piece of the gp41 molecule. E2 peptides have been shown to inhibit fusion as well. These studies led me to hypothesize that antibodies to E2 might interfere with HIV entry, and studies described in this application show that a variety of GBV-C E2 antibodies neutralize HIV infectivity in vitro. Immunization of rabbits, mice, and monkeys with recombinant GBV-C E2 protein elicits antibodies that react with E2 protein, but also react with a cellular-based molecule on HIV particles. This cellular molecule is not exposed on the surface of cells. Thus we hypothesize that GBV-C E2 protein mimics the structure of a cellular molecule that is enriched on HIV particles, and that binding to this antige decreases HIV infectivity. The purpose of this proposal is to: 1) generate tools that will allow further characterization of the E2 and HIV particle molecule recognized by these antibodies, and determine the optimal immunization method for raising antibodies to GBV-C E2, and 2) characterize and identify the cellular molecule involved in E2 antibody mediated neutralization. These studies will provide insight into a new method of generating a HIV vaccine, and may provide new molecules that can be targeted for the development of HIV treatments. Since the VA provides medical care to the largest single population of HIV-infected people in the United States, this research is highly relevant to the VA research mission.

描述（由申请人提供）： 事实证明，艾滋病毒疫苗的开发很困难；尽管最近的研究表明，对艾滋病毒的保护是可能的。在过去的16年中，在感染的HIV（和HIV未感染的）人类中发现了抗体，这些抗体在体外中和HIV的各种分离株。这些广泛中和的HIV抗体的鸡尾酒降低了感染人类的​​HIV病毒载量，并减少了HIV传播模型中的HIV传播。已经进行了这些HIV中和抗体的广泛表征，众所周知，这些抗体中的某些抗体是多性特异性的，可以识别出与病毒 - 细胞融合（GP41）有关的HIV糖蛋白上的隐藏区域，并且具有可能在HIV中发挥作用的细胞组成。到目前为止，您的主要局限性是用HIV GP41或细胞成分免疫后无法重复或有效产生它们。我发现一种常见的，显然是非病毒性的人类病毒（GB病毒C）在体外抑制了HIV复制，并且与没有GBV-C的人相比，与GBV-C共感染的HIV感染的人的寿命更长。我们发现GBV-C感染了包括CD4细胞在内的淋巴细胞，而其他人则发现GBV-C包膜糖蛋白E2 E2抑制了HIV融合，就像GP41分子的一部分一样。 E2肽也已被证明也抑制融合。这些研究使我假设对E2的抗体可能会干扰HIV的进入，并且在本申请中描述的研究表明，各种GBV-C E2抗体在体外中和HIV感染性中和。兔子的免疫 小鼠和具有重组GBV-C E2蛋白的猴子会引起与E2蛋白反应的抗体，但也与HIV颗粒上的基于细胞的分子反应。该细胞分子不暴露在细胞表面。因此，我们假设GBV-C E2蛋白模仿了富含HIV颗粒的细胞分子的结构，并且与该抗体的结合降低了HIV感染性。该提案的目的是：1）生成工具，这些工具将允许这些抗体识别的E2和HIV颗粒分子进一步表征，并确定提高对GBV-C E2抗体的最佳免疫方法，以及2）表征和鉴定涉及E2抗体介导的中性中性中性中性中性分层的细胞分子。这些研究将提供对一种新的生成HIV疫苗的新方法的见解，并可能提供可用于开发HIV治疗的新分子。由于VA为美国最大的艾滋病毒感染者提供医疗服务，因此这项研究与VA研究任务高度相关。