The Role of the Immune Response in Controlling the Size of the HIV Reservoir.

描述（由申请人提供）：hiv感染的个体积累了一个治疗耐药的、潜伏感染的静息CD4+ T细胞库。在缺乏高效抗逆转录病毒治疗（HAART）的情况下，被称为精英抑制者的一类特殊HIV感染者的病毒载量无法检测，并且具有较小的HIV库。有令人信服的证据表明，精英抑制者（ES）比治疗和未治疗的慢性进展者具有更高的抗HIV功能CTL活性。我们最近的数据提供了证据，证明ES中的CTL在体内对潜伏感染的静止CD4+ T细胞具有活性。具体来说，我们首次证明，与HAART患者相比，ES患者的整合HIV DNA水平显著降低，而非整合HIV DNA水平相对较高。这与CTL压力是一致的，因为与未整合的HIV DNA相比，整合的HIV蛋白表达效率更高。此外，我们有初步数据表明，潜伏感染的静止CD4+ T细胞表达HIV蛋白，但不允许传播感染，因此应该对CTL压力敏感。同时，我们通过体外潜伏期模型证明CTL对潜伏感染的静止CD4+ T细胞具有活性。因此，CTL靶点的范围比以前认为的要大，因为潜伏感染的细胞似乎可以成为CTL的靶点。在这项应用中，我们计划通过评估ES与HAART患者静息CD4+ T细胞中HIV RNA+细胞的频率来检测CTL压力的进一步证据。我们预计在ES中，HIV RNA+细胞归一化为整合的频率较低，因为我们预计大多数HIV RNA+细胞将表达蛋白质并受到CTL裂解。最后，我们将确定在ES的所有或一个子集中整合水平是否随着时间的推移而增加（正如我们的初步数据所表明的那样），以及整合水平的增加是否与ES中CTL功能的丧失相关。我们还考虑了另一种假设，即ES的整合水平可能随着时间的推移而增加，因为有缺陷的原病毒会积累。

DESCRIPTION (provided by applicant): HIV-infected individuals accumulate a reservoir of treatment-resistant, latently infected resting CD4+ T cells. A special category of HIV infected individuals called elite suppressors have undetectable viral loads in the absence of highly active antiretroviral therapy (HAART) and have a smaller HIV reservoir. There is compelling evidence that elite suppressors (ES) have higher functioning CTL activity against HIV than treated and untreated chronic progressors. Our recent data provide evidence that CTL in ES have activity against latently infected resting CD4+ T cells in vivo. Specifically, we demonstrate for the first time that ES patients have dramatically lower levels of integrated HIV DNA and a relatively large excess of unintegrated HIV DNA compared to HAART patients. This is consistent with CTL pressure since HIV proteins are expressed more efficiently from integrated compared to unintegrated HIV DNA. In addition, we have preliminary data that latently infected resting CD4+ T cells express HIV proteins but do not permit spreading infection and thus should be susceptible to CTL pressure. At the same time, we show with our in vitro model of latency that CTL have activity against latently infected resting CD4+ T cells. Thus, the range of CTL targets is greater than previously thought since it appears that latently infected cells can be targets of CTL. In this application, we plan to test for further evidence of CTL pressure by assessing the frequency of HIV RNA+ cells among resting CD4+ T cells in ES vs HAART patients. We expect the frequency of HIV RNA+ cells normalized to integration to be lower in ES because we expect the majority of HIV RNA+ cells will express protein and be subjected to CTL lysis. Finally, we will determine if integration levels increase over time (as suggested by our preliminary data) in all or a subset of ES and if an increase in integration levels correlates with a loss of CTL function in ES. We also consider the alternate hypothesis that integration levels may increase over time in ES because defective proviruses accumulate. PUBLIC HEALTH RELEVANCE: A special category of HIV infected individuals, called elite suppressors, control HIV viral load to undetectable levels in the absence of antiviral therapy. The proposed experiments investigate the mechanism behind the ability of elite suppressors to maintain a smaller reservoir. Our studies suggest that elite suppressors have immune activity against treatment resistant reservoir cells and may lead to future therapies that harness the immune response to reduce reservoir size in patients receiving antiviral therapy.