HIV-1 Gene Suppression by CD8+ T Cells

描述（由申请人提供）：由于HIV在宿主细胞中建立并持续处于潜伏状态，因此迄今为止尚未实现体内HIV复制的消除。尽管已经尝试激活和消除这些储存库，但目前使用的最有效的抗逆转录病毒疗法并不能根除潜伏状态的艾滋病毒。对于HIV，尚不清楚在体内如何诱导和维持原病毒潜伏期。需要更好地了解宿主免疫反应是否参与艾滋病毒潜伏期。我们已经确定，非细胞溶解性CD8抑制发生在病毒基因表达期间，并抑制病毒转录的起始。我们现在有证据表明，在原病毒潜伏期发生的相同表观遗传变化也会由于非细胞溶解性CD8抑制而发生。我们建议在这一新发现的基础上确定非细胞溶解性CD8抑制是否直接参与HIV潜伏期。我们将研究转录调控所需的染色质重塑分子事件，以确定非细胞溶解性CD8抑制与原病毒潜伏期之间的联系。对对CD8抑制具有相反敏感性的基因相关病毒对嵌合体的分析将确定耐药病毒表型是否来自潜伏期所需的分子变化。这项研究的结果除了可以立即改变候选HIV疫苗的设计和评估外，还可以更好地了解当前抗逆转录病毒药物的局限性。这项工作的潜在意义是，非细胞溶解性CD8 T细胞将有利于旨在降低峰值病毒血症和设定点的疾病修饰疫苗策略，但不会有利于预防性疫苗策略。本研究有两个具体目的：1。确定非溶细胞性CD8+ T细胞介导的HIV抑制是否导致HIV潜伏期。2. 确定与非细胞溶解性CD8耐药性相关的病毒遗传变化，并确定潜伏期的作用。

DESCRIPTION (provided by applicant): Elimination of HIV replication in vivo has not been achieved to date because HIV establishes and persists in a latent state in host cells. Although attempts have been made to activate and eliminate these reservoirs, the most potent antiretroviral regimens in use today do not eradicate HIV from its latent state. For HIV, it is not known how provirus latency is induced and maintained in vivo. A better understanding of whether host immune responses are involved in HIV latency is needed. We have determined that noncytolytic CD8 suppression occurs during the time of virus gene expression and inhibits the initiation of virus transcription. We now have evidence that the same epigenetic changes that occur during provirus latency also occur as a result of noncytolytic CD8 suppression. We propose to build upon this novel finding to determine if noncytolytic CD8 suppression is directly involved in HIV latency. The molecular events of chromatin remodeling required for transcriptional regulation will be examined to determine the linkage between noncytolytic CD8 suppression and provirus latency. Analyses of chimeras of genetically related pair of viruses with opposing sensitivities to CD8 suppression will determine if the resistant virus phenotype results from molecular changes required for latency. The results from this study can provide a better understanding of the current limitations of antiretrovirals, in addition to immediately altering candidate HIV vaccine design and evaluation. Potential implications of this work are that noncytolytic CD8 T cells would be of benefit for disease-modifying vaccine strategies aimed to reduce peak viremia and set point, but would not be of benefit for preventative vaccine strategies. This study has two specific aims: 1. Determine if noncytolytic CD8+ T cell mediated HIV suppression causes HIV latency. 2. Identify the viral genetic changes linked to noncytolytic CD8 resistance and determine the role of latency. PUBLIC HEALTH RELEVANCE: Noncytolytic CD8 T cell mediated suppression plays an important role in viral control in natural HIV infection and thus could be an important immune response to elicit by vaccination. Conversely, the elicitation of this immune response may be undesirable if a protective vaccination strategy is the goal. The results from this study will determine if induction of noncytolytic CD8 T cells would be beneficial in a protective vaccination strategy or whether it should be restricted to disease-modifying vaccine strategies.