ABSTRACT Depression is the most prevalent neuropsychiatric condition in IV infection and frequently associated with substance use disorders (SUD), including methamphetamine (METH) use disorder. Nevertheless, there is an alarming lack of information on the interactions between HIV, SUD, and depression, emphasizing a critical gap of knowledge on the mechanisms of HIV and/or METH impact on the development of depression. The present application is focused on the role of the inflammasome in this disease. Based on our preliminary results, we formulated the central hypothesis that HIV and/or METH-induced inflammasome activation primes for the development of depression. Mechanistically, we will focus on the dysregulation of the gut-brain axis in this process because the gut microflora is a potent activator of the inflammasome and a producer of a variety of mood-influencing metabolites and neurotransmitters. Moreover, there is strong recent evidence on the involvement of chronic neuroinflammatory responses and the disruption of the blood-brain barrier (BBB) influencing the development of depression. We propose to evaluate the following sequence of events in a novel humanized mouse model infected with HIV and exposed to METH: HIV infection/METH exposure → inflammasome activation → dysfunction of tissue barriers (the gut and the BBB) → neuroinflammation → depression. Successful completion of this proposal will meet the translation objective, which is to demonstrate that HIV infection and/or METH exposure contributes to, and accelerates, the pathomechanisms of depression via the alterations of the gut-brain axis, which involves inflammasome activation and chronic brain neuroinflammatory responses. The significance of our proposal is within its focus on the leading public health problem in people living with HIV (PLWH), namely depression. The mechanisms of HIV and/or METH-induced development of depression are largely unknown, making the proposed studies innovative and likely to generate unique data sets. The resulting discoveries may have significant epidemiological, economic, and social implications. Knowledge of the underlying mechanism(s) whereby HIV and METH prime individuals to depression may provide critically important and therapeutically relevant information to identify novel targets for pharmacological intervention. Our long-term goal is to characterize how HIV and METH contribute to the pathomechanisms of depression and, ultimately, prevent its development through a precision therapeutic intervention.