Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte-Mediated HIV Neuropathogenesis

Jaureguiberry‐Bravo, Matias; Wilson, Rebecca; Carvallo, Loreto; Berman, Joan W.

doi:10.2174/1570162x14666160324124132

Cited by 11 publications

(10 citation statements)

References 140 publications

(196 reference statements)

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“…Opioids have been shown in some studies to augment HIV neuropathogensis and their effects are still present in the current ART era . One mechanism by which opioids may increase HIV neuropathogenesis is by modulating the functions of immune cells . This is supported by the fact that these cells, including monocytes, express opioid receptors .…”

Section: Discussionmentioning

confidence: 99%

“…Opioid abuse is important in the context of HIV infection and neuropathogenesis since some studies have shown that HIV infected people who use opioids have increased CNS disease compared to infected non-opioid abusers [36–39]. The mechanisms by which opioids contribute to HIV neuropathogenesis are not fully understood, but regulation of immune cell functions is believed to be important [40–42].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Frontline Science: Buprenorphine decreases CCL2-mediated migration of CD14+CD16+ monocytes

Jaureguiberry‐Bravo

Lopez

Berman

2018

Journal of Leukocyte Biology

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HIV infection of the CNS causes neuroinflammation and damage that contributes to the development of HIV-associated neurocognitive disorders (HAND) in greater than 50% of HIV-infected individuals, despite antiretroviral therapy (ART). Opioid abuse is a major risk factor for HIV infection. It has been shown that opioids can contribute to increased HIV CNS pathogenesis, in part, by modulating the function of immune cells. HIV enters the CNS within two weeks after peripheral infection by transmigration of infected monocytes across the blood brain barrier (BBB). CD14 CD16 monocytes are a mature subpopulation that is increased in number in the peripheral blood of HIV-infected people. Mature monocytes can be productively infected with HIV, and they transmigrate preferentially across the BBB in response to CCL2, a chemokine elevated in the CNS and CSF of HIV-infected people even with ART. Buprenorphine, an opioid derivate, is an opioid replacement therapy for heroin addiction. It is a partial agonist of μ-opioid receptor and full antagonist of κ-opioid receptor. The effects of buprenorphine on CCL2-mediated CD14 CD16 monocytes transmigration across the BBB, a critical mechanism that promotes neuroinflammation and HAND, have not been characterized. We showed for the first time that buprenorphine decreases several steps of CCL2-mediated human mature monocyte transmigration. We propose that buprenorphine treatment in the context of HIV infection could serve a dual purpose, to treat opioid addiction and also to reduce neuroinflammation. Additionally, buprenorphine may be used as a treatment for HAND not only in the context of opioid abuse.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Frontline Science: Buprenorphine decreases CCL2-mediated migration of CD14+CD16+ monocytes

Jaureguiberry‐Bravo

Lopez

Berman

2018

Journal of Leukocyte Biology

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“…al. 2016 ). In S. pneumoniae -infected mice, morphine and/or Tat exposure significantly enhances immune cell trafficking into the brain via actions at TLR2 and TLR4 (Dutta and Roy 2015 ).…”

Section: Hiv Neuropathology In the Context Of Opioid Use Disorder – Cmentioning

confidence: 99%

“…In primary astrocytes, agonist-selective actions at MOR and KOR can be clearly demonstrated (Bohn et al 2000 ; Belcheva et al 2003 ; McLennan et al 2008 ; Hahn et al 2010 ), and we found that morphine, methadone, and buprenorphine differentially increase ROS and [Ca 2+ ] i alone or following Tat co-exposure (Fitting et al 2014b ). Morphine can enhance HIV-1-induced production of cytokines and specifically chemokines (El-Hage et al 2008a ; Dave 2012 ; El-Hage et al 2014 ), while other opioids including methadone, oxycodone, buprenorphine, and DAMGO can decrease inflammatory function and decrease monocyte migration (Boland et al 2014 ; Carvallo et al 2015 ; Jaureguiberry-Bravo et al 2016 ; Chilunda et al 2019 ).…”

Section: Questions Remaining – Future Directionsmentioning

confidence: 99%

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

Fitting

McRae

Hauser

2020

J Neuroimmune Pharmacol

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With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and μ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV. Graphical Abstract Blood-brain barrier and the neurovascular unit. With HIV and opiate co-exposure (represented below the dotted line), there is breakdown of tight junction proteins and increased leakage of paracellular compounds into the brain. Despite this, opiate exposure selectively increases the expression of some efflux transporters, thereby restricting brain penetration of specific drugs.

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“…OUD is important in the context of HIV infection, as several studies have reported that PLWH who use opioids are at a higher risk of developing neurological disorders compared to PLWH without OUD [15][16][17][18][19][20]. Opioids have been shown to upregulate the expression of CCR5 while downregulating the expression of its cognate β-chemokine production by acting through µ-opioid receptor in macrophages and microglia, thereby boosting the entry of R5 tropic viruses in these target cells [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Chronic morphine administration differentially modulates viral reservoirs in SIVmac251 infected rhesus macaque model

Acharya

Olwenyi

Thurman

et al. 2020

Preprint

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HIV persists in cellular reservoirs despite effective anti-retroviral therapy with rebound of viremia upon therapy interruption. Opioids modulate the immune system and suppress antiviral gene responses, which significantly impact people living with HIV (PLWH). However, the effects of opioids on viral reservoir remains elusive. Herein, we describe a morphine dependent SIVmac251 infected Rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs. RMs were ramped up with morphine (n=10) or saline (n=9) for two weeks to a final dosage of 5mg/kg administered twice daily, which was maintained for seven weeks, and then infected with SIVmac251. Combined anti-retroviral therapy (cART) was initiated in approximately half the animals in each group five weeks post-infection and morphine/saline administration continued for 10 months. Among drug naïve macaques, there were no differences in plasma/CSF viral load nor in cell-associated DNA/RNA loads. However, within the cART-suppressed macaques, there was a reduction in cell-associated DNA load, intact proviral DNA copy numbers, and inducible SIV reservoir in both peripheral blood and lymph nodes (LNs) of morphine-administered RMs compared to saline controls. Further, PBMCs of morphine administered RMs, a reduction in Th1 polarized CD4+ T cells and in LNs there was a reduction in the total Tfh and Th1 like Tfh cells were observed, indicating probably have impact on reduction of viral reservoirs. In distinction to PBMC and LNs, within the CNS size of latent SIV reservoirs was higher in the CD11b+ microglia/macrophages of morphine-dependent RMs. These data suggest that morphine plays a role in modulating SIV reservoirs, reduces the CD4+ T-cell reservoir in both peripheral blood and LNs, and increases microglia/macrophage reservoirs in CNS. These findings will aid in understanding of molecular mechanism(s) of opioid-mediated differential modulation of viral reservoirs and evaluation of therapeutic strategies to reduce/eliminate HIV reservoirs in opioid-dependent PLWH.Author summaryOpioids are commonly used as well as abused by HIV infected individuals, are known to suppress immune responses. However, their effects on modulating viral reservoir dynamics is not known. Here we developed a morphine dependent SIVmac251 infected rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs and immune cells. We found that there was no difference in viral loads or cell-associated DNA/RNA loads among morphine dependent vs. saline treated control macaques. On the other hand, when macaques were treated with cART, there was a reduction in SIV reservoirs both in periphery and lymphoid tissues in morphine administered RMs, and the size of latent SIV reservoir was higher in the CNS CD11b+ microglia/macrophages as compared to control macaques. Therefore, these new data form macaque models suggest that PLWH who suffering from opioid use disorders have higher reservoirs in CNS as compared to lymphoid system. Thus, through understanding these reservoirs among PLWH who uses opioids are critical for better designing HIV cure strategies.

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Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte-Mediated HIV Neuropathogenesis

Cited by 11 publications

References 140 publications

Frontline Science: Buprenorphine decreases CCL2-mediated migration of CD14+CD16+ monocytes

Frontline Science: Buprenorphine decreases CCL2-mediated migration of CD14+CD16+ monocytes

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

Chronic morphine administration differentially modulates viral reservoirs in SIVmac251 infected rhesus macaque model

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