Interplay of Autophagy Regulated Cell Death and HIV Pathogenesis in Substance Use Disorders (R21 Clinical Trial Not Allowed)

The notice of funding opportunity (NOFO) aims to support studies to expand our knowledge of mechanisms driving autophagy and to identify autophagy pathways that can be exploited to control HIV infection and pathogenesis of comorbities in the context of addictive substance use. The NOFO invites mechanistic studies and preclinical studies testing effects of compounds known to interfere with autophagy pathways on HIV infection and immune system. All studies must clearly address the intersection between HIV and substance use. Background: Autophagy is a ubiquitous mechanism involved in the lysosomal-mediated degradation of cellular components via autophagosomes engulfing the vacuoles and is a conserved mechanism of cellular defense against invading pathogens. Autophagy also contributes neuronal protective mechanisms in the CNS. Studies have shown that autophagy regulates presynaptic neurotransmission, and loss of neuronal autophagy leads to increased excitatory neurotransmission. It is also known that synaptic autophagy and neurotransmission are reciprocally regulated. For example, dopamine plays a significant role in enhancing autophagy mediated inflammatory responses via the D1R-Zn2+ signaling pathway. HIV-1 viral proteins can incite a cascade of neuroinflammatory response that leads to changes in glutamate receptor-mediated excitotoxicity, perturbation of synaptic homeostasis, and disrupted neuronal and glial function. Because all of these are tightly regulated by autophagy, it is critically important to understand the mode and the functional implications of autophagy and the connection with neurotransmission in the context of substance use disorder (SUD) and HIV. An important cellular feature of HIV pathogenesis is the migration of infected cells, including within the CNS. Autophagy machinery plays a key role in chemotactic cell migration by coordinating lipid flux and protein cargo transports. Alternatively, autophagy plays a dual role in HIV-1 replication and pathogenesis. Studies showed that autophagic activity is inversely correlated with HIV-1 production. Autophagy restricts HIV-1 infection by selectively degrading Tat in CD4+ T cells. HIV-1 proteins can directly induce cell death pathways such as apoptosis, pyroptosis and ferroptosis. Earlier studies suggest a link between ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, and reduced CD4+ cells following HIV infection. HIV infection may also induce T-cell apoptosis through an indirect mechanism of pyroptosis, a pro-inflammatory form of programmed cell death that is induced after abortive HIV infection on CD4+ T cells. As autophagy functions as a decisive process for cell death, these HIV-induced cell death pathways are tightly regulated by autophagic mechanisms. Additionally, pyroptotic cell death is a common occurrence under inflammatory conditions and follows on from the activation of procaspase-1 via formation of the inflammasome. The National Institute on Drug Abuse (NIDA) previously issued several funding announcements targeting inflammasome pathways in the context of HIV and SUD. Because the innate immune responses, inflammasome and autophagy regulations function like a two-way street, and autophagy is an integral immune system component as a main regulator of inflammasomes, the current NOFO aims to extend the line of inflammasome research, further expanding our knowledge of autophagic crosstalk activities on direct and/or in-direct cell death pathways to broaden the research scope of HIV innate immune responses in the context of SUD. Given that substance use induces significant impacts on the structure and function of CNS cells and circuits that underlie addiction behaviors, and HIV infections induced neuroinflammation that correlates with molecular and cellular adaptations, the interconnection between autophagy and molecular and cellular signatures in the context of SUD and HIV represents an under-explored research avenue. Understanding the roles of autophagy in HIV and SUD may open up new horizons for therapeutics, tools, and technology developments that leverage autophagy machinery and signaling pathways to mitigate neurological manifestations in people living with HIV/AIDS and SUDs. Research Questions: The NOFO encourages mechanistic pilot studies using in vivo and in vitro models. Research questions that aim to address how autophagy regulated HIV-induced cell death pathway may be part of an approach to target HIV harboring cells in CNS of people living with HIV (PLWH) and SUDs would be of interest. The research areas that are pertinent to this NOFO include, but are not limited to: Investigations of the interconnection and reciprocal regulation between synaptic autophagy and neurotransmission in the context of SUD and HIV. Understand autophagy regulated innate immune responses induced by HIV infections and addictive substances. Study how autophagy processes are involved in the changes in neuronal excitability, synaptic plasticity, neuron-glia communication, and neural circuit activity that contribute to SUD, HIV infection and viral reservoir persistence. Decipher autophagy machinery in HIV pathogenesis, with and without the presence of addictive substances. Specifically, the trafficking and processing of the core autophagy proteins, how autophagy regulates and coordinates chemotactic cell migration, and the downstream signaling cascades. Explore the role of autophagic regulation in viral and host transcriptional regulation in HIV neuropathogenesis, with and without the presence of addictive substances. Explore the role of autophagy in aging related biological processes under the influence of HIV and SUD. Develop tools and technology to harness autophagy to balance T-cell function to mitigate neuroinflammation induced by HIV and SUD. Delineate autophagic signaling mechanisms that regulate synaptic scaling to leverage pharmacological approaches suitable for restoring synaptic function in chronic neuroinflammatory states under the influence of SUD and HIV. Applications Not Responsive to this NOFO The following types of applications are not responsive to this NOFO and will be withdrawn prior to review: Applications that do not contain one aim or sub-aim focus on (1) exposure of addictive substances (opioids, cannabinoids, methamphetamine, amphetamine, cocaine, and nicotine), or (2) autophagy process and function relevant to addictive substance use. Applications focused solely on alcohol exposure.