HIV-associated neurocognitive disorder (HAND) remains highly prevalent in HIV infected individuals and represents a special group of neuropathological disorders, which are associated with HIV-1 viral proteins, such as transactivator of transcription (Tat) protein. Cocaine abuse increases the incidence of HAND and exacerbates its severity by enhancing viral replication. Perturbation of dopaminergic transmission has been implicated as a risk factor of HAND. The presynaptic dopamine (DA) transporter (DAT) is essential for DA homeostasis and dopaminergic modulation of the brain function including cognition. Tat and cocaine synergistically elevate synaptic DA levels by acting directly on human DAT (hDAT), ultimately leading to dysregulation of DA transmission. Through integrated computational modeling and experimental validation, key residues have been identified in hDAT that play a critical role in Tat-induced inhibition of DAT and induce transporter conformational transitions. This review presents current information regarding neurological changes in DAT-mediated dopaminergic system associated with HIV infection, DAT-mediated adaptive responses to Tat as well as allosteric modulatory effects of novel compounds on hDAT. Understanding the molecular mechanisms by which Tat induces DAT-mediated dysregulation of DA system is of great clinical interest for identifying new targets for an early therapeutic intervention for HAND.

与HIV相关的神经认知障碍（HAND）在受HIV感染的个体中仍然非常普遍，并且代表特殊的一组神经病理性疾病，与HIV-1病毒蛋白（例如转录反式激活蛋白（Tat）蛋白）有关。可卡因滥用会增加病毒复制，从而增加HAND的发生率并加剧其严重性。多巴胺能传递的扰动被认为是HAND的危险因素。突触前多巴胺（DA）转运蛋白（DAT）对于DA稳态和包括认知在内的脑功能的多巴胺能调节至关重要。Tat和可卡因通过直接作用于人DAT（hDAT）协同增高突触DA水平，最终导致DA传递失调。通过集成的计算模型和实验验证，在hDAT中已鉴定出关键残基，这些残基在Tat诱导的DAT抑制中起关键作用，并诱导转运蛋白构象转变。这篇综述提供了有关DAT介导的与HIV感染相关的多巴胺能系统的神经系统变化，DAT介导的对Tat的适应性反应以及新化合物对hDAT的变构调节作用的最新信息。了解Tat诱导DAT介导的DA系统失调的分子机制，对于识别HAND早期治疗干预的新靶点具有重大的临床意义。这篇综述介绍了有关DAT介导的与HIV感染相关的多巴胺能系统的神经系统变化，DAT介导的对Tat的适应性反应以及新化合物对hDAT的变构调节作用的最新信息。了解Tat诱导DAT介导的DA系统失调的分子机制，对于识别HAND早期治疗干预的新靶点具有重大的临床意义。这篇综述提供了有关DAT介导的与HIV感染相关的多巴胺能系统的神经系统变化，DAT介导的对Tat的适应性反应以及新化合物对hDAT的变构调节作用的最新信息。了解Tat诱导DAT介导的DA系统失调的分子机制，对于识别HAND早期治疗干预的新靶点具有重大的临床意义。