Humoral response to viral and self-antigens in HIV infection

HIV感染中对病毒和自身抗原的体液反应

• 批准号: 8664345
• 负责人: John H Elder
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-22 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664345
• 关键词: Adsorption; Affinity Chromatography; Antibodies; Antibody Formation; Antiviral Response; Antiviral Therapy; Autoantigens; Autoimmune Process; Binding; Biochemical; Biological Assay; Blocking Antibodies; CD4 Antigens; CD8B1 gene; Cells; Complex; Dependence; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Epitopes; Exhibits; Fc Receptor; Feline Immunodeficiency Virus; Felis catus; Gagging; Generations; Grant; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; Homologous Gene; Human; Immune response; Individual; Infection; Intervention; Ligands; Measures; Mutation; Nature; Patients; Relative (related person); Role; Serum; Site; T-Lymphocyte; Vaccines; Viral; Viral Load result; Viral load measurement; Viremia; Virus; Virus Receptors; cohort; improved; in vivo; outcome forecast; public health relevance; receptor; receptor binding; response; screening; success; uptake; vaccine development

DESCRIPTION: The disease prognosis for HIV positive individuals is markedly improved if viral loads are kept at a minimum. Some non-progressors appear to have an innate ability to control virus expression in the absence of antiviral therapies and it is generally assumed that this control of viremia is largely dictated by the humoral and/or cellular immune response to the virus. However, both non-progressors and rapid progressors exhibit substantial immune responses to HIV, with humoral antibody responses particularly directed at the major neutralization target, the viral envelope. Studies of the humoral antibody response associated with FIV infection has revealed the presence of antibodies to the primary binding receptor, CD134, in a high percentage of infected cats. Furthermore, these anti-CD134 antibodies blocked FIV infection ex vivo and their presence correlated with low/slow disease progression in vivo. Reactivity with CD134 occurs at a cryptic epitope that is only exposed when virus binds, thus avoiding potential autoimmune issues. The purpose of the present studies is to pursue characterization of the homologous anti-receptor antibodies against the HIV primary binding receptor, CD4 that we have identified in screening the sera of approximately 300 HIV-infected patients. We wish to determine whether there is a relationship between rate/extent of disease progression and generation of anti-CD4 antibody responses; and 2) whether a subset of anti-CD4 antibodies interfere with HIV infection. To this end, we propose the following Aims: 1). Use Immunoaffinity to purify anti-CD4 antibodies from patient serum and assess the influence of those antibodies on virus uptake into target cells; and 2) Continue screening of additional patient serum to assess anti-CD4,anti-SU, and anti-Gag humoral antibody responses as a function of rate/extent of disease progression, as measured by relative CD4+ and CD8+ T cell levels and viral load. The findings will increase our understanding of the nature of the antiviral response as it relates to protection and thus aid in development of more efficacious vaccine strategies.

描述：如果病毒载量保持在最低水平，HIV 阳性个体的疾病预后将显着改善。一些非进展者似乎具有在缺乏抗病毒治疗的情况下控制病毒表达的先天能力，并且通常认为这种病毒血症的控制很大程度上取决于对病毒的体液和/或细胞免疫反应。然而，非进展者和快速进展者都表现出对 HIV 的显着免疫反应，体液抗体反应特别针对主要中和目标，即病毒包膜。对与 FIV 感染相关的体液抗体反应的研究表明，大部分受感染的猫体内存在针对主要结合受体 CD134 的抗体。此外，这些抗 CD134 抗体可在体外阻断 FIV 感染，并且它们的存在与体内低/慢的疾病进展相关。与 CD134 的反应发生在一个隐秘的表位处，该表位仅在病毒结合时才会暴露，从而避免了潜在的自身免疫问题。本研究的目的是对针对 HIV 主要结合受体 CD4 的同源抗受体抗体进行表征，我们在筛选大约 300 名 HIV 感染者的血清时发现了这种抗体。我们希望确定疾病进展的速率/程度与抗 CD4 抗体反应的产生之间是否存在关系； 2) 抗 CD4 抗体的子集是否会干扰 HIV 感染。为此，我们提出以下目标：1）。使用免疫亲和力从患者血清中纯化抗 CD4 抗体，并评估这些抗体对病毒摄取到靶细胞中的影响； 2) 继续筛选额外的患者血清，以评估抗 CD4、抗 SU 和抗 Gag 体液抗体反应作为疾病进展速率/程度的函数，通过相对 CD4+ 和 CD8+ T 细胞水平和病毒载量进行测量。这些发现将增加我们对抗病毒反应本质的理解，因为它与保护有关，从而有助于开发更有效的疫苗策略。