Buprenorphine Increases HIV-1 Infection In Vitro but Does Not Reactivate HIV-1 from Latency

Abstract

Background: medication-assisted treatment (MAT) with buprenorphine is now widely prescribed to treat addiction to heroin and other illicit opioids. There is some evidence that illicit opioids enhance HIV-1 replication and accelerate AIDS pathogenesis, but the effect of buprenorphine is unknown. Methods: we obtained peripheral blood mononuclear cells (PBMCs) from healthy volunteers and cultured them in the presence of morphine, buprenorphine, or methadone. We infected the cells with a replication-competent CCR5-tropic HIV-1 reporter virus encoding a secreted nanoluciferase gene, and measured infection by luciferase activity in the supernatants over time. We also surveyed opioid receptor expression in PBMC, genital epithelial cells and other leukocytes by qPCR and western blotting. Reactivation from latency was assessed in J-Lat 11.1 and U1 cell lines. Results: we did not detect expression of classical opioid receptors in leukocytes, but did find nociception/orphanin FQ receptor (NOP) expression in blood and vaginal lymphocytes as well as genital epithelial cells. In PBMCs, we found that at physiological doses, morphine, and methadone had a variable or no effect on HIV infection, but buprenorphine treatment significantly increased HIV-1 infectivity (median: 8.797-fold increase with 20 nM buprenorphine, eight experiments, range: 3.570–691.9, p = 0.0078). Using latently infected cell lines, we did not detect reactivation of latent HIV following treatment with any of the opioid drugs. Conclusions: our results suggest that buprenorphine, in contrast to morphine or methadone, increases the in vitro susceptibility of leukocytes to HIV-1 infection but has no effect on in vitro HIV reactivation. These findings contribute to our understanding how opioids, including those used for MAT, affect HIV infection and reactivation, and can help to inform the choice of MAT for people living with HIV or who are at risk of HIV infection.

Virally Suppressed People Living with HIV Who Use Opioids Have Diminished Latency Reversal

“…Adding morphine alone did not result in the induction of HIV-1 expression from latent cells, nor did morphine influence HIV reactivation upon T cell activation via TCR engagement in vitro. These results are in agreement with reports from other groups showing morphine, heroin, buprenorphine and methadone had no effects on HIV-1 reactivation from T cell lines that harbor latent HIV [ 17 , 56 ]. Our data do contradict other studies reporting HIV-1 reactivation by morphine ] in the promonocytic cell line U1, which harbors repressed HIV-1, cocultured with microglia in the presence of morphine and LPS [ 57 ].…”

“…Although there are several reports of immune cells expressing classical opioid receptors, mu, delta and kappa receptors [ 58 , 59 , 60 , 61 ], there are numerous contradictory reports about opioid receptor expression and the impact of opioids on immune function [ 17 , 62 , 63 ]. We did not detect opioid receptor mRNA in human PBMCs, CD4+ T cells or monocyte-derived macrophages, and opioids had minimal effect on HIV-1 infection and replication in vitro.…”

“…However, the role opioids play in HIV progression is confounded by people with opioid use disorders being less adherent to antiretroviral therapy (ART) [ 13 , 14 , 15 ]. In vitro experiments have also implicated opioids in regulating HIV infection and replication in human macrophages, peripheral blood mononuclear cells and lymphocytes [ 16 , 17 ]. In vitro treatment of these cells with opioids, mainly morphine, augments HIV replication by increasing the expression of HIV-1 co-receptors CCR5 and CXCR4 [ 18 , 19 ].…”

Innate immune regulation in HIV latency models

“…We evaluated the impact of ART-mediated HIV suppression on cell-intrinsic antiviral responses in a primary CD4 + T cell model of HIV infection. We established a primary cell model of virologic suppression [ 54 ], which is similar to models from other laboratories [ 55 – 58 ]. This model allows analysis of HIV-infected cells in the context of low or no detectable HIV RNA expression as a proxy for HIV latency in patients undergoing ART.…”

Drugs of Abuse and Their Impact on Viral Pathogenesis

“…Retention on buprenorphine treatment was associated with maximal HIV suppression in opioid-dependent persons [70], although there are no reports on whether buprenorphine directly impacts HIV levels in vivo. A recent study found that buprenorphine resulted in more than an eight-fold increase of in vitro infection of PBMCs from uninfected individuals with an HIV reporter virus [71]. In contrast, in a murine model of HIV, viral levels were not increased, although cognitive impairment was reduced in the presence of buprenorphine [72].…”