IMMUNOLOGICAL AND VIRAL FACTORS ASSOCIATED WITH HIV-1 SUPERINFECTION

 描述(由申请人提供)：虽然HIV-1重复感染(SI)在其免疫系统可能已经有一些由HIV感染引起的免疫缺陷的个人中并不能真实地代表HIV-1阴性者接种疫苗的后果，但重叠感染和非重叠感染个人之间的免疫学和病毒学差异或在SI发生前后发生的事件可能有助于我们更好地了解保护性免疫反应，并指导合理的HIV疫苗设计和开发。以前关于细胞免疫反应和体液免疫反应在HIV SI中的作用的研究，对于它们在预防SI中的作用给出了相互矛盾的结果。此外，之前没有进行过任何研究 能够在已知的具有未连锁病毒的伙伴中识别SI，其中免疫反应和病毒在SI之前和之后都具有特征。我们希望通过分析从高危人群中的大量A和D亚型感染者中收集的样本来做出贡献，在这些人群中，早期的研究表明SI的发生率很高。我们建议使用一项正在进行的队列研究中已保存的标本，在和谐的阳性夫妇中鉴定连锁SI。此外，我们还将使用非常新的方法来检测SI，并将我们的免疫学研究建立在使用自体多肽和病毒的基础上。此外，据我们所知，还没有研究检查粘膜和先天免疫反应在预防SI中的作用，这一应用程序旨在填补这一空白。干扰素的作用最近被认为与传播瓶颈有关；这是否在SI中起作用还需要探讨。有机会调查SI病毒是否具有在初次感染期间传播的与干扰素耐药信息有关的类似于创始人病毒的特性，从而可能导致治疗和预防干预在这些研究中，我们将检验这样一种假设，即与未被重叠感染的匹配个体相比，在HIV-SI之前的个体中发现的先天和获得性免疫反应水平不足或水平较低，尤其是病毒被膜的中和抗体和结合抗体。这将是一项病例对照研究，以调查暴露/保护因素的影响，如中和抗体和T细胞亚群。对于某些其他分析，将在参与者的一个子样本上进行进一步的探索性测试，以生成假设。具体目标是：1)在持续的高危人群和感染艾滋病毒的夫妇中确定无关联感染的艾滋病毒SI。2)检测匹配的SI病例中的抗HIV抗体和CD8 T细胞反应--SI前后高危个体和有联系的夫妇的对照3)探索循环和/或粘膜天然免疫反应是否能预防HIV-1重叠感染

 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