Integrating preclinical models to develop converging mechanistic data in co-occurring HIV and substance use

物质使用障碍与艾滋病毒感染高度共存，近25%的艾滋病毒携带者需要 治疗。随着联合抗逆转录病毒疗法(CART)的成功，艾滋病毒相关死亡率 大幅下降。这导致了越来越多的慢性艾滋病毒感染者和接受CART治疗的人 美国的成年人。HIV感染和CART都可能与药物接触相互作用，改变神经生物学， 因此创造了一种行为和生物上截然不同的状况，并需要新的、有针对性的药物治疗 减少强迫性药物使用和高复吸倾向的策略 精神错乱。皮质纹状体谷氨酸系统是这些形式的行为不灵活的关键调节因素。 从内侧前额叶皮质到伏隔核的投射是恢复的关键媒介 毒品寻觅，一种复发的模式，以及不顾不良后果仍无法终止毒品寻觅， 一种强迫症的模式。在艾滋病毒患者群体和临床前模型中不断增长的文献表明 感染诱导的皮质纹状体谷氨酸系统的改变是HIV相关的一个因素 神经认知障碍。尽管如此，皮质纹状体谷氨酸系统改变的强有力的特征 在艾滋病毒感染和CART治疗中，缺乏具有电路和细胞类型特异性的药物。我们将充分利用 新的HIV感染小鼠模型的出现，并在(1)人源化小鼠模型中并行进行研究 成功地发育出类似人类的小胶质细胞，从而使进行性中枢神经系统感染 HIV，以及(2)感染嵌合病毒-EcoHIV的野生型小鼠。以确定当前行业是否 单独或组合的治疗影响行为或谷氨酸系统生物学的标准，子集 将接受比替格列韦、恩曲他滨和替诺福韦丙氨酰胺(B/F/TAF)治疗的小鼠。这 研究将使用多重原位杂交来检验基因和蛋白质表达是 HIV感染和CART小鼠模型中谷氨酸神经元和星形胶质细胞群的变化。我们还将 验证HIV感染和B/F/TAF相互作用调节星形胶质细胞和神经细胞钙信号的假设 在可卡因奖赏学习、可卡因恢复和强迫性类可卡因寻求过程中， 皮质纹状体星形胶质细胞和神经元的纤维光度测定法。展示在……中的作用 胶质细胞传递和谷氨酸能皮质纹状体神经元活性在减少强迫症或复发相关疾病中的作用 在小鼠身上寻找可卡因，我们将使用细胞和电路特异性的化学遗传操作。最后，我们将使用 用于调节谷氨酸释放和摄取的新型和临床前验证的药理工具 人源化、HIV感染和EcoHIV感染的小鼠以确定是否采取药物策略来减少 强迫和复发在感染和B/F/TAF治疗状态下同样有效。我的实验室会解决这个问题 通过与免疫学、艾滋病毒和药物研发领域的领导者合作，未得到满足的需求，使我们能够 为HIV感染中寻求药物的皮质纹状体谷氨酸调节提供全面、一致的数据。

Substance use disorders are highly comorbid with HIV infection, with nearly 25% of individuals with HIV needing treatment. With the success of combinatorial antiretroviral therapies (cART), HIV-associated mortality has substantially declined. This has resulted in a growing population of chronically HIV-infected and cART treated adults in the United States. Both HIV infection and cART may interact with drug exposure to alter neurobiology, thus creating a behaviorally and biologically distinct condition and requiring novel, targeted pharmacotherapeutic strategies to reduce the compulsive drug use and high relapse propensity that characterize substance use disorders. The corticostriatal glutamate system is a key regulator of these forms of behavioral inflexibility. Projections from the medial prefrontal cortex to the nucleus accumbens are critical mediators of reinstatement of drug seeking, a model of relapse, and the inability to terminate drug seeking despite adverse consequences, a model of compulsivity. A growing literature in both HIV patient populations and preclinical models has identified infection-induced alterations in the corticostriatal glutamate system as a contributor to HIV-associated neurocognitive disorders. Despite this, a robust characterization of corticostriatal glutamate system alterations in HIV infection and cART treatment, with circuit- and cell-type specificity, is lacking. We will capitalize on the advent of new mouse models of HIV infection and perform studies in parallel in (1) a humanized mouse model that successfully develops human-like microglia, thus enabling progressive central nervous system infection with HIV, and (2) wild-type mice infected with a chimeric virus – EcoHIV. To determine whether current industry standards of treatment impact behavior or glutamate system biology independently or in combination, a subset of mice will receive chronic bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) treatment. This research will use multiplexed in situ hybridization to test the hypothesis that gene and protein expression are altered in glutamate neurons and astrocyte populations in mouse models of HIV infection and cART. We will also test the hypothesis that HIV infection and B/F/TAF interact to regulate astrocyte and neuron calcium signaling during cocaine reward learning, cocaine reinstatement, and compulsive-like cocaine seeking via simultaneous fiber photometric assessment in corticostriatal astrocytes and neurons. To demonstrate a role for gliotransmission and glutamatergic corticostriatal neuron activity in reducing compulsive-like or relapse-related cocaine seeking in mice, we will use cell- and circuit-specific chemogenetic manipulations. Finally, we will use novel and preclinically-validated pharmacological tools for regulating glutamate release and uptake in humanized, HIV-infected and EcoHIV-infected mice to determine whether pharmacological strategies to reduce compulsivity and relapse are similarly effective in infected and B/F/TAF-treated states. My lab will address this unmet need through collaboration with leaders in the immunology, HIV, and drug discovery fields, enabling us to provide thorough, convergent data on corticostriatal glutamate regulation of drug seeking in HIV infection.