Identification and molecular characterization of SIV Vpr R50G mutation associated with long term survival in SIV-infected morphine dependent and control macaques

Rivera, Ivelisse; García, Yashira; Gangwani, Mohitkumar R.; Noel, Richard J.; Maldonado, Lucianette; Kumar, Anil; Rivera‐Amill, Vanessa

doi:10.1016/j.virol.2013.07.027

Cited by 4 publications

(3 citation statements)

References 54 publications

(69 reference statements)

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“…This deficiency highlights the major difficulties with studying drug abuse in a human population, especially among HIV patients, and the lack of animal models to study these interactions has limited the progression to understanding the interactions between HIV and morphine. Although there have been a number of studies on effects of morphine on SIV infection in macaques (Rivera-Amill et al 2010; Bokhari et al 2011; Spikes et al 2012; Rivera et al 2013; Hollenbach et al 2014), to our knowledge early pathogenesis within the gut has not been investigated. In order to take advantage of genetic tools and low cost of mice, we pursued an infectious model of HIV to combine with our established model of opioid abuse to overcome these limitations in the field.…”

Section: Discussionmentioning

confidence: 99%

An Infectious Murine Model for Studying the Systemic Effects of Opioids on Early HIV Pathogenesis in the Gut

Sindberg

Sharma

Banerjee

et al. 2014

J Neuroimmune Pharmacol

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Opioids are known to exacerbate HIV pathogenesis, however current studies have been limited by models of HIV infection. Given that HIV causes many systemic effects via direct infection of host cells as well as indirect bystander effects, it is important to establish a systemic infection model in a small animal so that genetic tools can be utilized to elucidate the mechanisms of action. In this study, we describe the systemic effects of EcoHIV infection, a modified HIV which can infect mouse cells, in conjunction with morphine. We observed that EcoHIV infection with opioid treatment induces bacterial translocation from the lumen of the gut into systemic compartments such as liver, which is similar to observations in human patients with LPS. Bacterial translocation corresponds with alterations in gut morphology, disorganization of the tight junction protein occludin, and a concurrent increase in systemic inflammation in both IL-6 and TNFα. Long term infection also had increased expression of inflammatory cytokines in the CNS when co-treated with morphine. Overall, we conclude that EcoHIV is an appropriate model to study the effects of opioids on HIV pathogenesis, including the HIV-induced pathology at early stages of pathogenesis in the gut.

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Section: Discussionmentioning

confidence: 99%

An Infectious Murine Model for Studying the Systemic Effects of Opioids on Early HIV Pathogenesis in the Gut

Sindberg

Sharma

Banerjee

et al. 2014

J Neuroimmune Pharmacol

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“…Within the United States, over 3,500 new infections involved IDU in 2015 (CDC, 2016), a year in which overall drug overdose deaths rose another 11%, the majority (63%) of which involved opioids (Rudd et al, 2016). The convergence of the HIV and opioid epidemics is particularly concerning given evidence that opioid usage increases the progression of HIV-1 to acquired immune deficiency syndrome (AIDS) and promotes neurocognitive impairment in humans and non-human primates (Bokhari et al, 2011; Bell et al, 1996, 2002, 2006; Chuang et al, 2005; Donahoe et al, 1993; Kumar et al, 2004, 2006; Rivera et al, 2013). Moreover, HIV-infected individuals are at risk for the development of neuropathic pain (Malvar et al, 2015) for which prescription opioids remain a common treatment (Kremer et al, 2016; Zilliox, 2017).…”

Section: Introductionmentioning

confidence: 99%

CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward

Gonek

McLane

Stevens

et al. 2018

Brain, Behavior, and Immunity

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The HIV-1 regulatory protein, trans-activator of transcription (Tat), interacts with opioids to potentiate neuroinflammation and neurodegeneration within the CNS. These effects may involve the C-C chemokine receptor type 5 (CCR5); however, the behavioral contribution of CCR5 on Tat/opioid interactions is not known. Using a transgenic murine model that expresses HIV-1 Tat protein in a GFAP-regulated, doxycycline-inducible manner, we assessed morphine tolerance, dependence, and reward. To assess the influence of CCR5 on these effects, mice were pretreated with oral vehicle or the CCR5 antagonist, maraviroc, prior to morphine administration. We found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine (2-64 mg/kg, i.p.) in non-tolerant mice. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Twenty-four hours following morphine administration, HIV-1 Tat significantly potentiated (∼3.5-fold) morphine-conditioned place preference and maraviroc further potentiated these effects (∼5.7-fold). Maraviroc exerted no measurable behavioral effects on its own. Protein array analyses revealed only minor changes to cytokine profiles when morphine was administered acutely or repeatedly; however, 24 h post morphine administration, the expression of several cytokines was greatly increased, including endogenous CCR5 chemokine ligands (CCL3, CCL4, and CCL5), as well as CCL2. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. These data demonstrate that CCR5 mediates key aspects of HIV-1 Tat-induced alterations in the antinociceptive potency and rewarding properties of opioids.

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“… • ↑ CD4+ and CD8+ T cells • ↑ CSF viral load • ↑ Infiltration of MDMs into the brain Rhesus macaques (Bokhari et al 2011 ). Viral load and HIV progression Mixture of SIV 17-EFr , SHIV KU _1B , SHIV 89.6P No Morphine (5 mg/kg, i.m., t.i.d., 20 weeks) • ↑ Viral load; ↓ CD4 counts • ↑ ROS with morphine + SIV Rhesus macaques (Perez-Casanova et al 2007 ; Perez-Casanova et al 2008 ) SIV gene mutation/evolution tat Mixture of SIV 17-EFr , SHIV KU _1B , SHIV 89.6P No Morphine (5 mg/kg, i.m., t.i.d., 20–56 weeks) • ↑ Viral load; ↓ CD4 counts • tat evolution—inverse correlation with SIV progression • ↓ tat diversity with morphine Rhesus macaques (Noel and Kumar 2006 ; Noel et al 2006b ) nef • ↑ Viral load; ↓ CD4 counts • ↓ nef evolution; no correlation with SIV progression ± morphine (Noel et al 2006a ) env • ↑ Viral load; ↓ CD4 counts • ↑ env evolution (V4 region) correlates with SIV progression + morphine • ↑ env evolution in CSF with morphine (Rivera-Amill et al 2007 , 2010b ) vpr • ↓ vpr evolution and/or Vpr R50G mutation—inverse correlation with SIV progression/mortality • ↓ vpr evolution with morphine (Noel and Kumar 2007 ; Rivera et al 2013 ) Neuronal injury, survival, oxidative stress gp120 HIV-1 LAV No Morphine (25 mg pellet, 5–7 days) • ↑ ROS during withdrawal • ↓ PSD95 during chronic and withdrawal • ↑ Sphingomyelin • ↓ Ceramide Mouse, gp120 tg b (Bandaru et al 2011 ) HIV No Morphine (37.5 mg s.c, 5 days) ...…”

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

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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Identification and molecular characterization of SIV Vpr R50G mutation associated with long term survival in SIV-infected morphine dependent and control macaques

Cited by 4 publications

References 54 publications

An Infectious Murine Model for Studying the Systemic Effects of Opioids on Early HIV Pathogenesis in the Gut

An Infectious Murine Model for Studying the Systemic Effects of Opioids on Early HIV Pathogenesis in the Gut

CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

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