Toward a Mouse Model of HIV-1 Infection and Drug Addiction

描述（由申请人提供）：这是一份竞争性续期拨款申请，要求继续支持DA017618项目“HIV-1感染和药物成瘾的小鼠模型”。在第一个资助周期中，我们完成了在常规小鼠中建立HIV-1感染模型的总体目标，并将其应用于HIV-1神经发病机制的研究。在没有明显的神经病理或病毒性脑炎的情况下，尽管小鼠具有有效的抗hiv -1免疫保护，但感染会诱发持久的认知缺陷。我们相信这些结果建立了一种轻度形式的HIV-1相关神经认知障碍（HAND）的动物模型。我们假设HAND的病因学不同于HIV诱导免疫缺陷的病因学，因为在免疫系统完整的情况下，在病毒感染早期观察到HAND。我们提出早期HAND （E-HAND）是由巨噬细胞对HIV-1感染的反应驱动的，但其程度受到有效抗病毒反应的限制。大脑中最初的HIV-1感染导致的神经系统损伤可能为免疫系统减弱后HAND的快速进展创造了条件，并可能代表早期脑损伤，在感染后期对抗逆转录病毒治疗反应不佳。我们提出了四个具体目标来验证这些假设：在目标1中，我们将定义认知/行为缺陷（E-HAND）在感染EcoHIV的免疫活性小鼠中与感染进展相关的总体参数。在目标2中，我们将定义HIV-1感染的时期，此时大脑最容易受到E-HAND的诱导；这些研究将验证一种假设，即对全身EcoHIV感染的适应性抗病毒反应限制了EcoHIV在大脑中的复制，而不是E-HAND。在Aim 3中，我们将验证在免疫系统完好的情况下，来自外周的巨噬细胞浸润，而不是病毒在大脑中的扩张，是导致E-HAND发生的原因。在Aim 4中，我们将确定E-HAND感染动物的免疫缺陷或明显神经病理诱导是否会促进向更严重形式的HAND过渡，以及E-HAND和严重HAND是否可以通过抗病毒治疗逆转。这些研究将评估早期艾滋病毒感染在大脑中引起的一些神经损伤可能是不可逆转的可能性。我们认为，鉴于抗逆转录病毒药物的日益广泛使用，拟议的研究是重要的，这些药物可以预防艾滋病的进展，但不能预防某些形式的HIV-1神经认知疾病。我们的长期目标是利用我们的模型来确定早期HIV-1感染期间经历的行为缺陷与非法药物滥用造成的伤害之间的生物学相互作用，从而设计出保护认知和运动功能的干预措施。

DESCRIPTION (provided by applicant): This is a competing renewal grant application requesting continuing support of the project DA017618 "Mouse model of HIV-1 infection and drug addiction". In the first funding cycle we accomplished our overall objective to develop a model of HIV-1 infection in conventional mice and applied it for studies on HIV-1 neuropathogenesis. Infection of mice induces lasting cognitive deficits that develop despite effective protective anti-HIV-1 immunity and in the absence of overt neuropathology or viral encephalitis. We believe these results establish an animal model of milder forms of HIV-1 Associated Neurocognitive Disorder (HAND). We hypothesize that the etiology of HAND is different from etiology of HIV induced immunodeficiency as indicated in HAND observed early in viral infection in the presence of an intact immune system. We propose that early HAND (E-HAND) is driven by responses of macrophages to HIV-1 infection but its extent is limited by effective antiviral responses. The damage to the nervous system resulting from initial HIV-1 infection in the brain may set the conditions for rapid progression of HAND after the immune system weakens and may represent early brain injury that is poorly responsive to antiretroviral treatments later in infection. Four Specific Aims are proposed to test these hypotheses: In Aim 1, we will define will define overall parameters of cognitive/behavioral deficits (E-HAND) in EcoHIV infected immunocompetent mice in relation to the progress of infection. In Aim 2, we will define the period of HIV-1 infection when the brain is most vulnerable to the induction of E-HAND; these studies will test the hypothesis that adaptive antiviral responses to systemic EcoHIV infection limit EcoHIV replication in the brain but not E-HAND. In Aim 3, we will test the hypothesis that infiltration of macrophages from the periphery, rather that expansion of virus in the brain, is responsible for the induction of E-HAND under intact immune system. In Aim 4, we will determine whether induction of immunodeficiency or overt neuropathology in infected animals with E-HAND promotes transition to more severe forms of HAND and whether E-HAND and severe HAND can be reversed by antiviral treatment. These studies will evaluate the possibility that some neurological damage caused by early HIV infection in the brain might be irreversible. We believe that the proposed studies are important in light of the increasingly wide use of antiretrovirals which prevent progression to AIDS but fail to prevent certain forms of HIV-1 neurocognitive disease. Our long-range goal is to employ our model to determine the biological interactions between the behavioral defects experienced during early HIV-1 infection and the injuries inflicted by illicit drug abuse to devise interventions that will preserve cognitive and motor function.