Therapeutic Immunization in Monkey Model of AIDS

高效抗逆转录病毒疗法(HAART)显著降低了HIV相关的死亡率和发病率，因为接受HAART治疗的大多数人在血浆中检测不到病毒RNA(&lt；50拷贝/毫升)。然而，HAART一直无法根除病毒，因为病毒隐藏在深层淋巴组织中，并且在停用 治疗后，病毒在这些人中的大多数中重新出现，并对CD4+T细胞群进行新的攻击。这种病毒的卷土重来对制定控制病毒复制的策略提出了另一项挑战，这些患者由于某种原因选择停止治疗。遏制病毒的一种有吸引力的方法是“治疗性免疫”。我们选择了一种恒河猴HIV/AIDS的神经致病模型，该模型是通过感染 SIV/17E-Fr和SIVdeltaB670的猕猴。这一模型已被证明在一半以上的受感染动物中会发展为SIV诱导的艾滋病和痴呆症。目前正在进行研究，以了解短期抗逆转录病毒治疗对血液和脑室病毒复制的影响，以及停止抗逆转录病毒治疗后复活病毒的性质。在这项应用中，我们将研究在药物治疗期间给予的疫苗是否能够诱导保护性免疫，从而防止病毒卷土重来，或者显著降低病毒的复制率，并无限期地推迟临床疾病的发生。鉴于我们的工作以及其他几个实验室的工作表明，减毒活疫苗在SIV/SIV猕猴艾滋病模型中提供了最佳保护，我们将使用减毒活疫苗来 测试治疗性免疫的概念。我们将给猕猴接种SIV/R71-Fr和SIVdeltaB670，并用抗逆转录病毒(PMPA)治疗它们。一组猕猴将接种减毒活病毒，而另一组未接种的猕猴将作为对照。我们将监测这两组患者的病毒复发、细胞和体液免疫反应、耐药情况以及疾病发展到临床期的情况 确定治疗性疫苗是否具有显著优势。在预期成功的情况下，我们将确定一种相对安全的治疗性免疫原灭活病毒颗粒是否也能产生类似的效果。这些研究将为治疗性免疫建立概念验证。如果成功，这种疫苗方法还将提供 一种替代永久感染后药物治疗的黯淡前景的选择。

The HIV-related mortality and morbidity has been significantly reduced by highly active antiretroviral therapy (HAART) because majority of the individuals receiving HAART develop undetectable viral RNA in plasma (<50 copies/ml). However HAART has been unable to eradicate the virus because virus hides in the deep lymphoid tissues and upon withdrawal of therapy, virus reappears in most of these individuals, with renewed attack on the CD4+T cell population. This viral resurgence poses another challenge to develop strategies to control virus replication in those patients who for some reason opt for treatment withdrawal. One attractive approach for the containment of virus is "therapeutic immunization". We have chosen a neuropathogenic model of HIV/AIDS in rhesus macaques that has been developed by infecting macaques with SIV/17E-Fr and SIVdeltaB670. This model has been shown to develop SIV-induced AIDS and dementia in more than half of the infected animals. Studies are underway to find out effect of short term antiretroviral therapy on virus replication in blood and cerebral compartment and also the nature of resurgent virus after cessation of antiretroviral therapy. In this application we will investigate whether a vaccine given during the period of drug therapy could induce protective immunity that would prevent virus from resurgence or significantly lower the rate of viral replication and delay the onset of clinical disease for indefinite time. In view of our work as well as work from several other laboratories that live attenuated vaccine confers best protection in SIV/SHIV macaque model of AIDS, we will use a live attenuated vaccine to test the concept of therapeutic immunization. We will inoculate the macaques with SIV/R71-Fr and SIVdeltaB670 and treat them with an antiretroviral (PMPA). A group of macaques will be immunized with live attenuated virus whereas another unvaccinated group will serve as controls. We will monitor viral resurgence, cellular and humoral immune responses, emergence of drug resistance and progression to clinical phase of the disease in these two groups and determine whether a therapeutic vaccine confers significant advantage. In anticipation of success, we will then determine whether a relatively safer therapeutic immunogen, inactivated virus particles, could also elicit similar effect. These studies will establish proof-of- concept for the therapeutic immunization. If successful, this vaccine approach would also provide an alternative to the dreary prospect of permanent post-infection drug therapy.