Eradication of HIV reservoirs in vivo

潜伏的或低水平的HIV-1持续宿主可能是根除感染的主要障碍。特别是，人们认为潜伏感染的T细胞可以携带整合病毒，这是目前治疗方法无法消除的。因此，如果治疗因任何原因停止，这个水库重新点燃感染。其他潜在的宿主，如大脑中的巨噬细胞或小胶质细胞，可以作为低水平病毒生产的长期来源。因此，必须识别和模拟消除这些储层的方法。该建议旨在使用体内模型，即最近描述的“BLT小鼠”来评估通过“诱导/根除”策略攻击潜伏库的方法。我们将进行研究来验证这样一个概念，即激活潜伏感染的细胞，然后引入特定的药物来杀死诱导新表达病毒的细胞，将提供一种在体内清除这些病毒库的方法。我们将通过以下三个具体目标来实现我们的目标：1)确定不同HIV毒株在BLT小鼠中建立的潜伏病毒库；2)测定抗hiv免疫毒素对体内潜伏库的影响；3)确定基因工程细胞毒性T细胞在体内影响病毒库的能力。本文提出的研究将开发一种有价值的体内系统来检测HIV潜伏期，并可能提供靶向免疫试剂在诱导潜伏病毒表达后促进清除HIV库的原理证明。

Latent or low-level persistent reservoirs of HIV-1 may be the chief hurdle to eradication of infection. In particular, it is thought that latently infected T cells can harbor integrated virus, which cannot be eliminated by current therapeutics. Therefore if therapy is discontinued for any reason, this reservoir rekindles infection. Additional potential reservoirs, such as macrophages or microglia in the brain could serve as long-lived sources of low-level virus production. It is thus imperative to identify and model means to eliminate these reservoirs. This proposal aims to use an in Vivo model, the recently described "BLT mouse" to assess methods to attack latent reservoirs by an "induction/eradication" strategy. We will perform studies to test the concept that activation of latently infected cells, followed by introduction of specific agents designed to kill cells induced to newly express virus, will provide a means of purging these resevoirs in vivo. We will accomplish our goals through the following three Specific Aims: 1) Define the reservoirs of latent virus established by different HIV strains in BLT mice; 2) Determine the effects of anti-HIV immunotoxin on latent reservoirs in vivo; 3) Determine the capacity of genetically engineered cytotoxic T cells to impact viral reservoirs in vivo. The studies proposed herein will develop a valuable in vivo system to examine HIV latency, and may provide proof-of-principle that targeted immunoreagents may facilitate clearance of HIV reservoirs following induction of expression of the latent virus.