This study is designed to address the goals of the RFA “Exploiting Genomic or Nucleomic Information to
Understand HIV Latency in Individuals with Substance Use Disorders” that can “understand HIV latency in
individuals with substance use disorders." To meet this challenge, in the R61 phase, we propose to identify the
biomolecular interactions between cellular activation pathways, epigenetic controls, and HIV integration patterns
that are impacted by chronic exposure from the conventional opioid therapeutics morphine and fentanyl. We also
propose to investigate whether chronic exposure of an innovative G protein signaling biased agonist SR-17018,
of which similar acting compounds are predicted to preserve opioid-induced analgesia and avoid respiratory
suppression, cause similar or distinct cell-HIV alterations as conventional opioids. Findings from these studies
will provide experimental guidance for our R33 phase studies.
In the R33 stage, we will utilize clinical samples available from persons with HIV and who are terminally-ill and
in our well-characterized Last Gift cohort and: (i) received well-characterized opioids (primarily morphine) for
analgesia during their illness, (ii) choose to stop their therapy before they die, (iii) experienced viral rebound, and
(iv) provided their entire bodies soon after death (<4 hours to autopsy) to advance novel HIV treatments and a
cure. Viral, cell, and tissue samples from the Last Gift cohort will be used to address whether opioid exposure in
vivo is associated with similar patterns of activation, genomic, epigenetic, and latency alterations uncovered in
the R61 phase of our studies. Furthermore, we propose to determine if chronic opioid exposure during active in
vivo HIV infection modulates dynamics of HIV diversification upon halting of anti-retroviral treatment and alters
replenishment of the HIV reservoir and HIV integration in circulating T cells and anatomical tissues, such as
various brain regions, lymph nodes, spleen and terminal ileum associated lymphoid tissues.
Our experimentally complementary R61 and R33 research stages will provide insights into mechanism(s)
underlying the effects of opioids on HIV infection and latency and will reveal targets for development of
pharmacologic interventions aimed to interrupt HIV integration and latency impacted by opioid use.