CD8+ T cell mediated inhibition of HIV-1 replication in Elite Suppressors

描述（由申请人提供）：精英抑制者是HIV-1感染患者，在没有抗逆转录病毒治疗的情况下维持病毒载量<50拷贝/ml。我们最近首次表明，可以从这些个体中分离出具有复制能力的病毒，这表明对具有复制能力的HIV-1进行免疫控制是可能的。这些患者的控制机制尚未确定，但我们已经表明，在许多ES中，优越的体液免疫不是控制的原因，也不是对HIV-1感染的内在抵抗力。我们已经证明，来自这些患者的原病毒也没有更高水平的APOBEC 3G/F介导的高突变。综上所述，似乎优越的hiv特异性细胞免疫在精英抑制者的病毒血症控制中起着关键作用。虽然CD8+ T细胞介导的控制机制尚不清楚，但已有研究表明精英抑制者和进行性疾病患者具有相似的hiv特异性CTL频率。然而，最近有研究表明，来自精英抑制者的未受刺激的CD8+ T细胞，而不是进行性疾病患者，能够控制自身CD4+ T细胞中实验室HIV-1株的复制。这是一个生理模型，因为CD8+ T细胞在被用于实验之前没有被激活，CD4+ T细胞处理并呈递HIV抗原（与在培养细胞中添加肽相反）。本建议的目的是确定CD8+ T细胞介导的对这种复制能力病毒的控制是如何实现的。我们计划确定参与这种控制的CD8+ T细胞的主要亚群。我们还将区分细胞毒性杀死靶细胞和非细胞毒性介导的病毒复制抑制。我们将定义CD8+ T细胞介导的控制动力学，并确定Nef介导的MHC I类蛋白下调是否是病毒用来逃避病毒复制控制的机制。这项工作将对开发可用于改善HIV-1感染者的HIV特异性免疫反应的疫苗具有重要意义。这可能使一些患者在没有抗逆转录病毒治疗的情况下长时间控制病毒。公共卫生相关性：由于病毒复制并破坏免疫系统，大多数感染HIV-1的患者CD4细胞计数下降，表现为艾滋病。一组独特的未经治疗的hiv -1感染患者，被称为精英抑制者（ES），能够完全控制病毒，不会发展成艾滋病（1-3）。该项目计划确定来自ES的CD8+ T细胞如何控制病毒；研究结果可能适用于研制有效的HIV-1疫苗。

DESCRIPTION (provided by applicant): Elite suppressors are HIV-1 infected patients who maintain viral loads of <50 copies/ml without antiretroviral therapy. We have recently shown for the first time that replication competent virus can be isolated from some of these individuals suggesting that immunologic control of replication competent HIV-1 is possible. The mechanism of control has yet to be defined in these patients, but we have shown that superior humoral immunity is not the cause of control in many ES and neither is an intrinsic resistance to HIV-1 infection. We have shown that provirus from these patients also do not have higher levels of APOBEC 3G/F mediated hypermutation. Taken together it appears that superior HIV-specific cellular immunity plays a key role in the control of viremia in elite suppressors. While the mechanism of CD8+ T cell mediated control is unknown, it has been shown that elite suppressors and patients with progressive disease have similar frequencies of HIV-specific CTL. However, it has recently been shown that unstimulated CD8+ T cells from elite suppressors, but not patients with progressive disease, are able to control the replication of a laboratory strain of HIV-1 in autologous CD4+ T cells. This is a physiological model since the CD8+ T cells are not activated prior to being used in the assay and the CD4+ T cells process and present HIV antigens (as opposed to peptides being added to the cells in culture). The objective of this proposal is to determine the mechanisms by which this CD8+ T cell mediated control of this replication competent virus is achieved. We plan to identify the major subset of CD8+ T cells involved in this control. We will also distinguish between cytotoxic killing of target cells and non-cytotoxic mediated suppression of viral replication. We will define the kinetics of the CD8+ T cell mediated control and determine whether Nef mediated down regulation of MHC class I proteins is a mechanism used by the virus to evade this control of viral replication. This work will be important for the development of vaccines that can be used to improve the HIV specific immune responses in HIV-1 infected individuals. This may allow some patients to control the virus without antiretroviral therapy for prolonged periods of time. PUBLIC HEALTH RELEVANCE: Most patients infected with HIV-1 will develop a drop in their CD4 counts and frank AIDS as the virus replicates and destroys the immune system. A unique group of untreated HIV-1-infected patients, termed Elite Suppressors (ES) are able to completely control the virus and do not develop AIDS (1-3). This project plans to determine how CD8+ T cells from ES control the virus; the results may be applicable to the development of an effective HIV-1 vaccine.