Controlling HIV-1 Replication in Macrophages: Cellular Regulation of Tat Expression

血液中的单核细胞和组织中的巨噬细胞是人体免疫系统的清道夫细胞。它们是最早感染艾滋病毒的细胞之一，并在细胞的一生中（可能长达数年）携带病毒。单核细胞仅在低频率感染，而组织中的巨噬细胞可以大量感染，并且可以显著促进病毒的产生。目前的有效联合疗法无法清除这些细胞中的病毒，对这种细胞类型的疗效有限。目前还没有专门针对这些重要病毒库中的HIV感染的治疗方法。我们发现，在巨噬细胞中HIV感染的实验室模型中，感染在几周内从活跃的和生产性的转变为慢性的和非生产性的。这种变化的特征是病毒重要的调节蛋白之一Tat的减少。在这个项目中，我们的目标是确定细胞如何诱导病毒生长的这种变化。这可能会导致通过靶向细胞蛋白而不是病毒蛋白来控制这些重要细胞中的HIV的新方法。控制巨噬细胞中的感染并防止病毒扩散到其他细胞，将有助于解决患者停止或中断治疗时病毒迅速反弹的问题，并有助于长期治疗和管理，最终将病毒从体内根除。

Monocytes in the blood and macrophages in the tissues are the scavenger cells of the body's immune system. They are among the first cells to become infected with HIV and harbour the virus for the lifetime of the cell, which can be up to several years. While monocytes are only infected at low frequency, macrophages in tissues can be infected in high numbers and can contribute significantly to virus production. Current potent combination therapies are unable to clear the virus from these cells and have limited efficacy in this cell type. There are no treatments which specifically target HIV infection in these important viral reservoirs. We have found that in a laboratory model of HIV infection in macrophages, the infection changes from active and productive to chronic and non-productive over the course of several weeks. This change is characterised by a decrease in one of the virus' important regulatory proteins, Tat. In this project, we aim to determine how the cells induce this change in the virus' growth. This may lead to novel ways in which HIV could be controlled in these important cells by targeting cellular rather than viral proteins. Controlling infection in macrophages and preventing spread of the virus to other cells would assist with the problem of the virus rebounding rapidly when patients stop or interrupt therapy and would help with long term treatment and management, leading to eventual eradication of the virus from the body.