Analysis of HIV-1 in mucosal tissue in elite suppressors

描述(由申请人提供)：精英抑制者是HIV-1感染患者，他们在没有抗逆转录病毒治疗的情况下保持病毒载量为50拷贝/毫升。尽管病毒复制得到了很好的控制，但这些患者仍然存在残留的病毒血症，这是由潜伏感染的包含有复制能力的HIV-1的CD4+T细胞的存在确定的。 有趣的是，ES患者外周血中这些潜伏感染细胞的频率远低于病毒载量无法检测到的抑制性HAART方案的患者。这可能表明ES可能是导致根除这些细胞的策略的最佳候选者。只有在ES中这些细胞的总负担要低得多的情况下，这才是正确的。因此，我们建议观察ES中的两个不同的粘膜部位。研究表明，在HAART患者中，肠道相关淋巴组织(GALT)中潜伏感染的CD4T细胞的频率是外周CD4+T细胞的10倍。我们想要确定这种关系在ES中是否成立。我们还将观察这些患者肺部潜伏感染的CD4+T细胞的频率，以便更好地了解ES中感染细胞的总负担。 我们最近还提供了证据，表明在ES的血浆中存在的HIV-1持续复制和进化的HIV-1水平非常低。从外周CD4+T细胞获得的病毒进化很少，这意味着其他隔室中的CD4+T细胞是导致血浆变异的正在进行的复制和进化的来源。通过分析从每个隔室获得的序列，我们将能够确定患者体内正在进行的复制的来源。 这项工作将是重要的，因为它可能表明ES是通过根除潜伏感染的CD4+T细胞来潜在地治愈HIV-1感染的研究的最佳候选者。 与公共卫生相关：大多数感染HIV-1的患者在病毒复制和破坏免疫系统时会出现他们的CD4计数下降和坦率的艾滋病，然而一组独特的未经治疗的HIV-1感染患者，称为精英抑制者(ES)，能够完全控制病毒，不会发展为艾滋病(1-3)。该项目计划测量这些患者体内存在的感染细胞的数量，并确定来自不同组织的病毒之间的关系。这一结果可能适用于制定根除艾滋病毒-1的战略。

DESCRIPTION (provided by applicant): Elite suppressors are HIV-1 infected patients who maintain viral loads of <50 copies/ml without antiretroviral therapy. Despite this excellent control of viral replication, these patients continue to have residual viremia as determined by the presence of latently infected CD4+ T cells that contain replication-competent HIV-1. Interestingly, the frequency of these latently infected cells in peripheral blood is much lower in ES than in patients on suppressive HAART regimens with undetectable viral loads. This might suggest that ES may be the best candidates for strategies that could lead to eradication of these cells. This would only hold true if the total burden of these cells was much lower in ES. We therefore propose to look at two different mucosal sites in ES. Studies have suggested that the frequency of latently infected CD4 T cells in the gut associated lymphoid tissue (GALT) is ten times higher than the frequency in peripheral CD4+ T cells in patients on HAART. We want to determine whether this relationship holds true in ES. We will also look at the frequency of latently infected CD4+ T cells in the lungs of these patients so as to have a better approximation of the total burden of infected cells in ES. We have also recently provided evidence of ongoing HIV-1 replication and evolution of the very low level of HIV-1 present in the plasma of ES. There was very little evolution of the virus obtained from peripheral CD4+ T cells implying that CD4+ T cells in some other compartment are the source of the ongoing replication and evolution that lead to the plasma variants. By analyzing the sequence obtained from each compartment we would be able to determine the source of ongoing replication in the patients. This work will be important because it may suggest that ES are the best candidates for studies that could potentially cure HIV-1 infection by the eradication of latently infected CD4+ T cells. 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, however 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 measure the number of infected cells present in these patients and to determine the relationship between viruses from different tissues. The results may be applicable to the development of strategies for the eradication of HIV-1.