IMMUNOLOGICAL AND VIRAL FACTORS ASSOCIATED WITH HIV-1 SUPERINFECTION

与 HIV-1 重复感染相关的免疫和病毒因素

• 批准号: 8916318
• 负责人: PONTIANO KALEEBU
• 金额: $ 13.48万
• 依托单位: UGANDA VIRUS RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916318
• 关键词: Activities of Daily Living; Antibodies; Antiviral Agents; Autologous; Binding; Bioinformatics; Biological Assay; Blood; CD8B1 gene; Case-Control Studies; Cells; Cellular Immunity; Cellular Immunology; Cohort Studies; Collaborations; Communities; Conflict (Psychology); Couples; Data; Data Set; Defensins; Dendritic Cells; Development; Epidemic; Epitopes; Event; Fishes; Frequencies; General Population; HIV; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV vaccine; HIV-1; Health; Humoral Immunities; Immune; Immune response; Immune system; Immunology; Individual; Infection; Inflammatory; Interferons; Intervention; Laboratories; Lead; Link; Measures; Mediating; Molecular Cloning; Molecular Virology; Morbidity - disease rate; Natural Immunity; Natural Killer Cells; Participant; Peptides; Persons; Phenotype; Population; Prevention; Production; Property; Protease Inhibitor; Reporting; Research; Resistance; Role; Rural; Sampling; Scientist; Sexually Transmitted Diseases; Source; Specimen; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Time; Training; Vaccination; Vaccine Design; Vaccines; Viral; Virus; Work; adaptive immunity; base; case control; chemokine; cohort; cytokine; follow-up; high risk; high risk behavior; insight; mortality; neutralizing antibody; next generation sequencing; novel; prevent; prophylactic; prospective; sex; superinfection; tool; transmission process; vaccine development

 DESCRIPTION (provided by applicant): Though HIV-1 superinfection (SI) in an individual whose immune system may already have some immune deficiencies caused by the HIV infection does not truly represent the consequences of vaccination in an HIV-1 negative person, immunological and virological differences between superinfected and non- superinfected individuals or events occurring around the time of SI could help us to better understand protective immune responses and guide rational HIV vaccine design and development. Previous studies looking at the role of both cellular and humoral immune responses in HIV SI have provided conflicting results on their role is preventing SI. In addition no previous study has been able to identify SI in known partners with unlinked viruses where both immune responses and virus are characterized before and after SI. We want to contribute by analysing samples being collected from a large cohort of subtype A and D infected individuals within high risk cohorts where earlier studies show high rates of SI. We propose to identify linked SI among concordant positive couples using already stored specimens from an on-going cohort study. We will in addition employ very novel assays to detect SI and base our immunology studies on using autologous peptides and viruses. In addition, to our knowledge, no studies have examined the role of mucosal and innate immune responses in protection against SI, a gap this application proposes to fill. The role of IFN has been recently implicated in the transmission bottleneck; whether this has a role in SI need to be explored. There is an opportunity to investigate whether SI viruses have properties similar to founder viruses transmitted during primary infection in relation to IFN-resistant information that could lead to therapeutic and prophylactic interventions In these studies we will test the hypothesis that insufficient or low levels of both innate and adaptive immune responses, particularly neutralizing antibodies and binding antibodies to the viral envelope, are found in individuals prior to HIV-SI when compared to matched individuals who do not become superinfected. This will be a case control study to investigate the effect of exposures / protective factors such as neutralizing antibodies and T-cell subsets. For certain other assays further exploratory tests to generate hypotheses will be carried out on a sub-sample of the participants. The Specific Aims are: 1) Identify HIV SI in ongoing high risk populations and in HIV infected couples with unlinked infections. 2) Examine anti-HIV antibody and CD8 T cell responses in matched SI case-controls of high risk individuals and in linked couples before and after SI 3) Explore if circulating and/or mucosal innate immune responses protect against HIV-1 superinfection

 描述（申请人提供）：虽然HIV-1重叠感染（SI）在免疫系统可能已经有一些由HIV感染引起的免疫缺陷的个体中并不能真正代表HIV-1阴性者接种疫苗的后果，免疫学和病毒学的差异之间的重叠感染和非在SI前后发生的重叠感染个体或事件可以帮助我们更好地理解保护性免疫反应，并指导合理的HIV疫苗设计和开发。以前的研究都在寻找细胞和体液免疫反应在艾滋病毒SI的作用提供了相互矛盾的结果，他们的作用是防止SI。此外，以前没有研究 能够在具有非关联病毒的已知伴侣中识别SI，其中免疫应答和病毒在SI之前和之后都被表征。我们希望通过分析从高风险队列中的A和D亚型感染个体的大型队列中收集的样本来做出贡献，早期研究显示SI的发生率很高。我们建议使用来自正在进行的队列研究的已经储存的标本在一致的阳性夫妇中识别连锁SI。此外，我们将采用非常新颖的检测方法来检测SI，并将我们的免疫学研究建立在使用自体肽和病毒的基础上。此外，据我们所知，没有研究检查粘膜和先天免疫应答在保护免受SI中的作用，这是本申请提出填补的空白。干扰素的作用最近已牵连在传输瓶颈，这是否有SI的作用需要探讨。有机会研究SI病毒是否具有与在初次感染期间传播的创始者病毒相似的性质，这与可能导致治疗和预防干预的IFN抗性信息有关。在这些研究中，我们将检验先天性和适应性免疫应答，特别是中和抗体和病毒包膜结合抗体不足或水平低的假设，与没有双重感染的匹配个体相比，在HIV-SI之前的个体中发现。这将是一项病例对照研究，旨在研究暴露/保护因素（如中和抗体和T细胞亚群）的影响。对于某些其他试验，将对参与者的子样本进行进一步探索性检验以生成假设。具体目标是：1）在持续高危人群和无关联感染的HIV感染夫妇中识别HIV SI。2)在SI之前和之后，检查高风险个体的匹配SI病例对照和连锁夫妇中的抗HIV抗体和CD 8 T细胞应答3）探索循环和/或粘膜先天免疫应答是否保护免受HIV-1双重感染