Circuitry- and cell-specific exploration of CB1R positive allosteric modulators in neuroHIV

About This Grant

Project Summary Human immunodeficiency virus type 1 (HIV-1) currently affects over 38 million people worldwide. With combined antiretroviral therapy (cART), HIV-1 is no longer a death sentence but a chronic disease with an inflammatory component. HIV-1 virus enters the central nervous system (CNS) early in infection, and while cART effectively suppresses viral replication in peripheral tissue, the CNS remains vulnerable. As cART does not cross the blood- brain barrier, the prevalence of mild to moderate cognitive impairments, known as HIV-1-associated neurocognitive disorders (HAND), remain high (50%). Brain regions specifically vulnerable to HIV include the fronto-hippocampal system, involving deficits in learning and memory behaviors. The release of viral proteins (i.e. Tat, Nef, gag) from HIV-1 infected brain resident cells plays a significant role in the underlying HAND neuropathology, including lasting changes in neuronal excitability, inflammatory processes, and synaptic communication. The endocannabinoid (eCB) system has attracted interest as a target for treating neurodegenerative disorders due to its potential neuroprotective, anti-inflammatory, and neurotrophic properties. However, due to psychoactive side effects, the therapeutic potential of cannabinoid type 1 receptor (CB1R) agonists is limited. Therefore, efforts are now focused on alternative targets of the eCB system for its therapeutic potential, including allosteric modulators. Published studies suggest that CB1R positive allosteric modulators (PAMs), including ZCZ011, GAT229, and ABD1236, are promising candidates as they can enhance CB1R activity indirectly without producing psychoactive effects, tolerance, or dependence. Additionally, as disease can alter eCB signaling, the use of PAMs may help to compensate and return the CNS to its normal state. Our preliminary data demonstrate neuroprotective effects of ZCZ011 against HIV-1 Tat-induced excitotoxicity as well as improvement of recognition memory in HIV-1 Tat transgenic mice. GAT229 has been shown to reduce behavioral signs and proinflammatory cytokines in rodent models of disease (e.g. neuropathic pain, Huntington’s disease); and preliminary data for ABD1236 demonstrate enhanced eCB signaling. We will test an innovative hypothesis that HIV-induced alterations in the mPFC→HPC neural circuitry predict deficits in mice performing a working memory task, which can be prevented by positive allosteric modulation of the CB1R. To achieve this goal, we will use well-established mouse models of neuroHIV/HIV and propose three aims. Aim 1 will determine how CB1R PAMs alter neuronal activity in the mPFC→HPC neural circuitry in vivo of HIV-1 Tat transgenic mice performing a working memory task. Aim 2 will determine the effects of HIV on eCB-mediated short-term synaptic plasticity in the mPFC→HPC circuitry of HIV-1 Tat transgenic and EcoHIV-infected mice ex vivo. Aim 3 will determine whether CB1R PAMs protective effects against EcoHIV-induced toxicity in vivo are mediated via actions at CB1R-expressing glia or neurons. This work will provide a foundation for characterizing the role of alternative targets of the eCB system in modulating memory circuitry in the context of HIV.