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.