Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs

Abstract

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.

Keywords: HIV; immune system; opioid use disorders; opioids; replication; reservoir.

Figure 1

Main opioid-, human- and HIV-related factors affecting cell–opioid interactions that underlie the heterogeneity in biological responses (and thereby in scientific findings). Each opioid molecule and the three classical G-protein-coupled opioid receptors (the µ-MOR-, κ-KOR-, and δ-opioid receptor) plus the fourth nociception receptor largely vary in terms of affinity and binding patterns. These receptors are differentially expressed in several cell types and activate distinct intracellular pathways. Being full agonist (such as morphine, fentanyl, and methadone), partial agonist (such as buprenorphine) or antagonist also implies different binding properties that facilitate unique intracellular signaling. Large intra- and inter-individual variation in response to the same dose and molecule exists depending also on epigenetic modifications and single-nucleotide polymorphisms at receptors sites or in enzymes involved in opioid metabolism. Further, pharmacokinetic variability and differential tissue penetration lead to large variation in peak concentrations, duration of exposure, potency, biophase, and intercompartmental distribution, which are also dependent on the route of administration. Opioid receptors differentially undergo homologous and heterologous desensitization, which can decrease the responses to opioid agonists according to dose and length of exposure. Lastly, HIV itself could affect the expression and splicing pattern of opioid receptors.

Figure 2

Opioids and HIV reservoir: summary of the main molecular mechanisms of interaction. Opioids could enhance HIV infectivity and replication through upregulation of HIV co-receptors (CCR5 and CXCR4) and by downregulating MIP-1b, the natural chemokine competing for CCR5. Opioids can also impair several intracellular innate antiviral responses based on IFN genes, restriction factors such as APOBEC3G/F and MxB, anti-HIV miRNAs and the intracellular pathways activated by TLRs; this would eventually result in favoring the synthesis of HIV strong-stop DNA and reverse transcription DNA as well as replication and integration. Chronic opioid exposure could induce cAMP production: increased intracellular levels of cAMP can activate proteins such as CREB which eventually could bind to the 5′LTR of HIV genome to stimulate viral replication. Lastly, opioids can increase the systemic and tissue-specific inflammatory milieu by immunomodulating properties and by worsening microbial translocation. This immuno-asset could eventually favor HIV reservoir maintenance and expansion by antigen-driven proliferation of latently infected cells and clonal expansion. Legend: MIP-1b, Macrophage Inflammatory Proteins 1 beta; CCR5, Cysteine–Cysteine Chemokine Receptor 5; CXCR4, C-X-C motif chemokine receptor type 4; IFN, interferon; miRNAs, micro RNAs; cAMP, Cyclic adenosine monophosphate; CREB, cAMP-response element binding protein cellular transcription factor; TLRs, Toll-like receptors.

Figure 3

Opioid exposure in a sample of participants from the Last Gift project. The figure illustrates the frequency of different prescribed opioids among a sample of 23 participants from the Last Gift projects (upper panel), the cumulative exposure (in months) to each medical opioid, and the overall number of opioids that have been prescribed per individual during the last 20 years (lower panel).