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CD8+ T细胞是否能够控制巨噬细胞中的HIV复制，以及它们是否能够在巨噬细胞被有效感染时杀死这些靶细胞。我们还计划确定CD4+ T细胞是否能够通过直接杀伤活性或细胞因子分泌来抑制巨噬细胞和CD4+ T细胞中的病毒复制。最后，我们将确定效应CD4+和CD8+ T细胞是否能够杀死潜伏感染的CD4+ T细胞

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 hypemutation. 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 unkown, 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 determine whether CD8+ T cells are capable of controlling HIV replication in macrophages and whether they can kill these target cells when they are productively infected. We also plan to determine whether CD4+ T cells are capable of suppressing viral replication in macrophages and CD4+ T cells by direct killing activity or by cytokine secretion. Finally we will determine whether effector CD4+ and CD8+ T cells are capable of killing latently infected CD4+ T cells 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. This will also have major implications for strategies for HIV-1 eradication since clearance of latently infected cells is facilitated by effecor T cell responses.