Category Archives: HIV/AIDS

Activation of GPR55 induces neuroprotection of hippocampal neurogenesis and immune responses of neural stem cells following chronic, systemic inflammation.

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Brain, Behavior, and Immunity

“New neurons are continuously produced by neural stem cells (NSCs) within the adult hippocampus. Numerous diseases, including major depressive disorder and HIV-1 associated neurocognitive disorder, are associated with decreased rates of adult neurogenesis. A hallmark of these conditions is a chronic release of neuroinflammatory mediators by activated resident glia.

Recent studies have shown a neuroprotective role on NSCs of cannabinoid receptor activation. Yet, little is known about the effects of GPR55, a candidate cannabinoid receptor, activation on reductions of neurogenesis in response to inflammatory insult.

In the present study, we examined NSCs exposed to IL-1β in vitro to assess inflammation-caused effects on NSC differentiation and the ability of GPR55 agonists to attenuate NSC injury.

Taken together, these results suggest a neuroprotective role of GPR55 activation on NSCs in vitro and in vivo and that GPR55 provides a novel therapeutic target against negative regulation of hippocampal neurogenesis by inflammatory insult.”

 https://www.ncbi.nlm.nih.gov/pubmed/30465881
https://www.sciencedirect.com/science/article/pii/S0889159118303246?via%3Dihub

Cannabinoids and reduced risk of hepatic steatosis in HIV-HCV co-infection: paving the way for future clinical research

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“Whether or not cannabis itself or cannabinoids contained in it may help to reduce hepatic steatosis in HIV-HCV coinfected patients remains an open question. The existing body of knowledge on the interactions between cannabis and the liver suggest a protective effect of cannabinoids on insulin resistance, diabetes, and NAFLD in the general population. Clinical research with randomized study designs is needed to evaluate the efficacy and safety of cannabis-based pharmacotherapies in HIV-HCV coinfected patients. Targeting the endocannabinoid system seems essential to differently manage several pathological conditions such as intestinal inflammation, obesity, diabetes and fatty liver disease. However, to date, few drugs have been tested in clinical trials. CB1-antagonists and CB2 agonists appear to be viable therapeutic options that need to be explored for the management of liver diseases. As HCV cure rates are coming close to 100% in the era of direct-acting antivirals, it is especially important to be able to identify modifiable risk factors of complications and death in HIV-HCV coinfected patients, as well as possible levers for intervention. Given the persistence of metabolic risk factors after HCV eradication, cannabis-based therapies need to be evaluated both as preventive and therapeutic tools in patients living with or at risk of liver steatosis, possibly in combination with existing conventional approaches.”

https://www.tandfonline.com/doi/full/10.1080/14787210.2018.1473764

Interferon- α-mediated Activation of T Cells from Healthy and HIV-infected Individuals is Suppressed by Δ 9 -Tetrahydrocannabinol

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Journal of Pharmacology and Experimental Therapeutics

“HIV patients routinely use medicinal cannabinoids to treat neuropathic pain, anxiety, and HIV-associated wasting. However, Δ 9 -Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in cannabis, suppresses T cell function and secretion of interferons, both critically important in the anti-viral immune response.

Interferon- α (IFN α), a key cytokine in T cell activation and peripheral control of HIV infection, can potentiate responsiveness to IL-7, a crucial homeostatic cytokine for peripheral T cell maintenance. . The objective of this investigation was to compare the response of T cells to stimulation by IFNα and IL-7 in T cells from healthy and HIV+ donors in the absence and presence of THC.

T cells from healthy and HIV+ donors were stimulated in vitrowith IFN α and IL-7 in the absence and presence of THC followed by measurements of signaling events through IFNAR, IFN α-induced expression of IL-7Rα, cognate signaling through IL-7R, and on IL-7-mediated T cell proliferation by flow cytometry and RT-qPCR. CD8+ T cells from HIV+ donors showed a diminished response to IFN α-induced pSTAT1 compared to CD8+ T cells from healthy donors while CD4+ T cells from HIV+ donors and healthy donors were comparable. Treatment with IFN α promoted IL-7R expression and potentiated IL-7-induced STAT5 phosphorylation to augment IL-7-mediated proliferation by T cells from healthy and HIV+ donors. Finally, HIV+ donors exhibited reduced sensitivity to THC-mediated suppression by IFN α and IL-7-mediated stimulation compared to healthy donors.

These results further support THC as immune suppressive while identifying putatively beneficial aspects of cannabinoid-based therapies in HIV+ patients.

https://www.ncbi.nlm.nih.gov/pubmed/30026298
http://jpet.aspetjournals.org/content/early/2018/07/19/jpet.118.250308

Marijuana Use Is Not Associated With Progression to Advanced Liver Fibrosis in HIV/Hepatitis C Virus-coinfected Women.

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“Marijuana (hereafter “tetrahydrocannabinol [THC]”) use has been associated with liver fibrosis progression in retrospective analyses of patients with chronic hepatitis C (HCV). We studied long-term effects of THC on fibrosis progression in women coinfected with human immunodeficiency virus (HIV)/HCV enrolled in the Women’s Interagency HIV Study (WIHS).

CONCLUSIONS:

In this large cohort of HIV/HCV-coinfected women, THC was not associated with progression to significant liver fibrosis. Alcohol use was independently associated with liver fibrosis, and may better predict fibrosis progression in HIV/HCV-coinfected women.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967608/

https://academic.oup.com/cid/article/63/4/512/2595097

Marijuana smoking does not accelerate progression of liver disease in HIV-hepatitis C coinfection: a longitudinal cohort analysis.

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“Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons.

In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection.”

https://www.ncbi.nlm.nih.gov/pubmed/23811492

“To conclude, in this first prospective evaluation of liver disease progression among HIV-HCV infected persons, we could not demonstrate any important effect of marijuana on liver disease outcomes. A causal association is unlikely: hazard ratios were weak and most importantly were attenuated when accounting for temporality in the exposure-disease relationship and there was no dose-response relationship. It is likely that previous studies have been biased by reverse causality as patients use more marijuana to relieve symptoms as liver disease progresses.”

https://academic.oup.com/cid/article/57/5/663/312934

Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer.

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“The true incidence of anorexia secondary to human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and cancer is not well classified owing to the fact that there is a lack of standardized definitions and recent clinical data in these settings.

Dronabinol, or Δ-9-tetrahydrocannabinol, is a synthetic molecule that closely mimics the action of Cannabis sativa L., a naturally occurring compound activated in the central nervous system by cannabinoid receptors.

Dronabinol exerts its effects by directly acting on the vomiting and appetite control centers in the brain, which in turn increases appetite and prevents vomiting.

In the USA, dronabinol is currently available in two dosage formulations – oral capsule and oral solution. While the oral capsule was initially approved by the US Food and Drug Administration in 1985, the recent approval of the oral solution in 2016 presents an “easy-to-swallow” alternative for patients using or intending to use dronabinol.

Dronabinol is indicated in adult patients with HIV/AIDS for the treatment of anorexia and weight loss. However, there is no approved indication in the setting of cancer-related anorexia and weight loss. This review aims at presenting available data on the use of oral dronabinol in the management of anorexia and weight loss in HIV/AIDS and cancer, as well as characterizing and highlighting the pharmacotherapeutic considerations of the newest formulation of dronabinol.”

 https://www.ncbi.nlm.nih.gov/pubmed/29670357
https://www.dovepress.com/dronabinol-oral-solution-in-the-management-of-anorexia-and-weight-loss-peer-reviewed-article-TCRM

Heavy Cannabis Use Associated With Reduction in Activated and Inflammatory Immune Cell Frequencies in Antiretroviral Therapy–Treated Human Immunodeficiency Virus–Infected Individuals

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Journals“Cannabis is a widely used drug in the United States, and the frequency of cannabis use in the human immunodeficiency virus (HIV)–infected population is disproportionately high. Previous human and macaque studies suggest that cannabis may have an impact on plasma viral load; however, the relationship between cannabis use and HIV-associated systemic inflammation and immune activation has not been well defined.

Heavy cannabis users had decreased frequencies of human leukocyte antigen (HLA)-DR+CD38+CD4+ and CD8+ T-cell frequencies, compared to frequencies of these cells in non-cannabis-using individuals. Heavy cannabis users had decreased frequencies of intermediate and nonclassical monocyte subsets, as well as decreased frequencies of interleukin 23– and tumor necrosis factor-α–producing antigen-presenting cells.

Conclusions

While the clinical implications are unclear, our findings suggest that cannabis use is associated with a potentially beneficial reduction in systemic inflammation and immune activation in the context of antiretroviral-treated HIV infection.”

https://www.ncbi.nlm.nih.gov/pubmed/29471387

https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/cix1116/4869752?redirectedFrom=fulltext

Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain.

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“Chronic pain is common in the United States and prescribed opioid analgesics use for noncancer pain has increased dramatically in the past two decades, possibly accounting for the current opioid addiction epidemic. Co-morbid drug use in those prescribed opioid analgesics is common, but there are few data on polysubstance use patterns.

We explored patterns of use of cigarette, alcohol, and illicit drugs in HIV-infected people with chronic pain who were prescribed opioid analgesics.

Almost half of the sample of people with HIV and chronic pain reported current prescribed opioid analgesic use (N = 372, 47.1%). Illicit drug use was common (N = 505, 63.9%), and cannabis was the most commonly used illicit substance (N = 311, 39.4%).

In multivariate analyses, only cannabis use was significantly associated with lower odds of prescribed opioid analgesic use (adjusted odds ratio = 0.57; 95% confidence interval: 0.38-0.87).

Conclusions/Importance: Our data suggest that new medical cannabis legislation might reduce the need for opioid analgesics for pain management, which could help to address adverse events associated with opioid analgesic use.”

https://www.ncbi.nlm.nih.gov/pubmed/29338578

http://www.tandfonline.com/doi/abs/10.1080/10826084.2017.1416408?journalCode=isum20

HIV-infected cannabis users have lower circulating CD16+ monocytes and IP-10 levels compared to non-using HIV patients.

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“Chronic immune activation and elevated numbers of circulating activated monocytes (CD16) are implicated in HIV-associated neuroinflammation.

The objective was to compare the level of circulating CD16 monocytes and interferon-γ-inducible protein 10 (IP-10) between HIV-infected cannabis users (HIV+MJ+) and non-cannabis users (HIV+MJ-), and determine whether in vitro Δ-Tetrahydrocannabinol (THC), a constituent of cannabis, affected CD16 expression as well as IP-10 production by monocytes.

RESULTS:

HIV+MJ+ donors possessed a lower level of circulating CD16 monocytes and serum IP-10, compared to HIV+MJ- donors. Further, monocytes from HIV+MJ+ donors were unable to induce CD16 expression when treated with in vitro IFNα, while HIV-MJ- and HIV+MJ- donors displayed pronounced CD16 induction, suggesting anti-inflammatory effects by cannabis.

CONCLUSIONS:

Components of cannabis, including THC, may decelerate peripheral monocyte processes that are implicated in HIV-associated neuroinflammation.”   https://www.ncbi.nlm.nih.gov/pubmed/29194121

http://journals.lww.com/aidsonline/Abstract/publishahead/HIV_infected_cannabis_users_have_lower_circulating.97348.aspx

“Medical Cannabis May Improve Neurocognitive Disorder in Patients With HIV. Medical marijuana could help prevent the development of neurocognitive disorders in patients with HIV, according to a new study. Tetrahydrocannabinol (THC), the prominent compound in marijuana, was found to slow the process of neurodegeneration — a condition common in about half of all patients with HIV — according to a study from researchers at Michigan State University (MSU).” https://www.specialtypharmacytimes.com/news/medical-cannabis-may-improve-neurocognitive-disorder-in-patients-with-hiv

“Marijuana may help HIV patients keep mental stamina longer. Norbert Kaminski, director of Michigan State University‘s Institute for Integrative Toxicology, has found that a chemical in marijuana, known as THC, can potentially slow the process of mental decline that can occur in up to 50 percent of HIV patients.” https://medicalxpress.com/news/2017-12-marijuana-hiv-patients-mental-stamina.html

“New Research Says A Chemical in Marijuana May Help HIV Patients Maintain Their Mental Fortitude. “The patients who didn’t smoke marijuana had a very high level of inflammatory cells compared to those who did use. In fact, those who used marijuana had levels pretty close to a healthy person not infected with HIV.”” http://game360.co/2017/12/new-research-says-chemical-marijuana-may-help-hiv-patients-maintain-mental-fortitude/

“Cannabis could prevent mental decline in up to 50 percent of HIV sufferers, new research reveals. Patients who use marijuana have fewer inflammatory white blood cells, which are involved in the immune system, a study found. This could save infected people from mental decline, which affects up to 50 percent of sufferers due to ongoing inflammation in the brain as a result of the immune system constantly fighting the virus. Lead author Professor Norbert Kaminski from Michigan State University, said: ‘Those who used marijuana had [inflammatory cell] levels pretty close to a healthy person not infected with HIV.'” http://www.dailymail.co.uk/health/article-5174379/Cannabis-prevent-mental-decline-HIV-sufferers.html

“Marijuana may help increase mental strength in HIV patients”  http://www.timesnownews.com/health/article/marijuana-may-help-increase-mental-strength-in-hiv-patients/145504

Monoacylglycerol lipase inhibitor JZL184 prevents HIV-1 gp120-induced synapse loss by altering endocannabinoid signaling.

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Neuropharmacology

“Monoacylglycerol lipase (MGL) hydrolyzes 2-arachidonoylglycerol to arachidonic acid and glycerol. Inhibition of MGL may attenuate neuroinflammation by enhancing endocannabinoid signaling and decreasing prostaglandin (PG) production. Almost half of HIV infected individuals are afflicted with HIV-associated neurocognitive disorder (HAND), a neuroinflammatory disease in which cognitive decline correlates with synapse loss. HIV infected cells shed the envelope protein gp120 which is a potent neurotoxin that induces synapse loss. Here, we tested whether inhibition of MGL, using the selective inhibitor JZL184, would prevent synapse loss induced by gp120. The number of synapses between rat hippocampal neurons in culture was quantified by imaging clusters of a GFP-tagged antibody-like protein that selectively binds to the postsynaptic scaffolding protein, PSD95. JZL184 completely blocked gp120-induced synapse loss. Inhibition of MGL decreased gp120-induced interleukin-1β (IL-1β) production and subsequent potentiation of NMDA receptor-mediated calcium influx. JZL184-mediated protection of synapses was reversed by a selective cannabinoid type 2 receptor (CB2R) inverse agonist/antagonist. JZL184 also reduced gp120-induced prostaglandin E2 (PGE2) production; PG signaling was required for gp120-induced IL-1β expression and synapse loss. Inhibition of MGL prevented gp120-induced synapse loss by activating CB2R resulting in decreased production of the inflammatory cytokine IL-1β. Because PG signaling was required for gp120-induced synapse loss, JZL184-induced decreases in PGE2 levels may also protect synapses. MGL presents a promising target for preventing synapse loss in neuroinflammatory conditions such as HAND.”

https://www.ncbi.nlm.nih.gov/pubmed/29061509

http://www.sciencedirect.com/science/article/pii/S0028390817304902?via%3Dihub