Cannabinoid Neuroimmune Modulation of SIV Disease

Molina, Patricia E.; Amedee, Angela M.; LeCapitaine, Nicole; Zabaleta, Jovanny; Mohan, Mahesh; Winsauer, Peter J.; Stouwe, Curtis Vande

doi:10.1007/s11481-011-9301-8

Cited by 53 publications

(52 citation statements)

References 80 publications

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“…In our studies using SIV-infected male rhesus macaques, chronic daily administration of Δ 9 -THC (0.32 mg/kg twice a day) produced a greater retention of body mass than chronic daily administration of vehicle (Molina et al 2011a; Molina et al 2011b). Conversely, Δ 9 -THC-treated female macaques failed to gain body weight during the course of the study (Amedee et al 2014a).…”

Section: Introductionmentioning

confidence: 62%

“…However, a similar protective effect was not observed in female macaques (Amedee et al 2014a), suggesting a possible drug-sex steroid interaction and highlighting the need for further studies focusing on sex-specific cannabinoid effects on SIV disease. Among the possible mechanisms responsible for modulation of disease progression in male macaques are attenuation of localized tissue inflammatory responses and viral replication (Molina et al 2011a) as discussed below and summarized in Table 2.…”

Section: Introductionmentioning

confidence: 99%

“…The serum cholesterol, HDL and LDL levels were lower in the Δ 9 -THC treated diabetic rats compared to untreated rats. This could partly be explained by the anti-inflammatory effects rendered by Δ 9 -THC (Ehrhart et al 2005; Molina et al 2011a). Cannabidiol, a non-psychotropic component of marijuana, has also been shown to significantly reduce the incidence of diabetes in non-obese diabetic mice (Weiss et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model

Molina

Amedee

Winsauer

et al. 2015

J Neuroimmune Pharmacol

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HIV-associated mortality has been significantly reduced with antiretroviral therapy (ART), and HIV infection has become a chronic disease that frequently coexists with many disorders, including substance abuse (Azar et al. 2010; Phillips et al. 2001). Alcohol and drugs of abuse may modify host-pathogen interactions at various levels including behavioral, metabolic, and immune consequences of HIV infection, as well as the ability of the virus to integrate into the genome and replicate in host cells. Identifying mechanisms responsible for these interactions is complicated by many factors, such as the tissue specific responses to viral infection, multiple cellular mechanisms involved in inflammatory responses, neuroendocrine and localized responses to infection, and kinetics of viral replication. An integrated physiological analysis of the biomedical consequences of chronic alcohol and drug use or abuse on disease progression is possible using rhesus macaques infected with simian immunodeficiency virus (SIV), a relevant model of HIV infection. This review will provide an overview of the data gathered using this model to show that chronic administration of two of the most commonly abused substances, alcohol and cannabinoids (Δ9-Tetrahydrocannabinol; THC), affect host-pathogen interactions.

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Section: Introductionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model

Molina

Amedee

Winsauer

et al. 2015

J Neuroimmune Pharmacol

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“…The fact that miR-532-5p is an antiviral miRNA induced in response to WNV KUN infection is the key new finding of our study. The differential expression of this miRNA was previously observed in response to infection with chikungunya virus (CHIKV) (51) and simian immunodeficiency virus (SIV) (56). However, the direct antiviral role of miR-532-5p against these and other viruses has not yet been demonstrated.…”

Section: Discussionmentioning

confidence: 98%

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

Slonchak

Shannon

Pali

et al. 2016

J Virol

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West Nile virus (WNV) is a mosquito-transmitted flavivirus that naturally circulates between mosquitos and birds but can also infect humans, causing severe neurological disease. The early host response to WNV infection in vertebrates primarily relies on the type I interferon pathway; however, recent studies suggest that microRNAs (miRNAs) may also play a notable role. In this study, we assessed the role of host miRNAs in response to WNV infection in human cells. We employed small RNA sequencing (RNA-seq) analysis to determine changes in the expression of host miRNAs in HEK293 cells infected with an Australian strain of WNV, Kunjin (WNV KUN ), and identified a number of host miRNAs differentially expressed in response to infection. Three of these miRNAs were confirmed to be significantly upregulated in infected cells by quantitative reverse transcription (qRT)-PCR and Northern blot analyses, and one of them, miR-532-5p, exhibited a significant antiviral effect against WNV KUN infection. We have demonstrated that miR-532-5p targets and downregulates expression of the host genes SESTD1 and TAB3 in human cells. Small interfering RNA (siRNA) depletion studies showed that both SESTD1 and TAB3 were required for efficient WNV KUN replication. We also demonstrated upregulation of mir-532-5p expression and a corresponding decrease in the expression of its targets, SESTD1 and TAB3, in the brains of WNV KUN -infected mice. Our results show that upregulation of miR-532-5p and subsequent suppression of the SESTD1 and TAB3 genes represent a host antiviral response aimed at limiting WNV KUN infection and highlight the important role of miRNAs in controlling RNA virus infections in mammalian hosts. IMPORTANCEWest Nile virus (WNV) is a significant viral pathogen that poses a considerable threat to human health across the globe. There is no specific treatment or licensed vaccine available for WNV, and deeper insight into how the virus interacts with the host is required to facilitate their development. In this study, we addressed the role of host microRNAs (miRNAs) in antiviral response to WNV in human cells. We identified miR-532-5p as a novel antiviral miRNA and showed that it is upregulated in response to WNV infection and suppresses the expression of the host genes TAB3 and SESTD1 required for WNV replication. Our results show that upregulation of miR-532-5p and subsequent suppression of the SESTD1 and TAB3 genes represent an antiviral response aimed at limiting WNV infection and highlight the important role of miRNAs in controlling virus infections in mammalian hosts. W est Nile virus (WNV) is a mosquito-transmitted flavivirus associated with outbreaks of encephalitis in humans and horses around the world (1). The most significant WNV outbreaks have occurred in North America, where a highly pathogenic strain of WNV emerged in New York in 1999. This strain rapidly spread to all the states and by 2011 had infected an estimated 1.8 million people, causing close to 360,000 illnesses and ϳ1,300 deaths (2). The majority of ...

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“…Historically, marijuana use has been associated with impaired memory and other measures of neurocognitive functioning 44,45 . However, recent evidence has emerged which indicates that agonists of the cannabinoid receptor type 2 (CB 2 ) have therapeutic potential in a variety of pathologic conditions involving chronic inflammation and immune activation, including HIV-1 infection 46–50 . It is unclear from our data if marijuana use actually provided a neuroprotective effect or if it too showed confounding from other factors.…”

Section: Discussionmentioning

confidence: 99%

Neurocognitive Dysfunction in HIV-Infected Youth: Investigating the Relationship with Immune Activation

et al. 2016

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Background HIV-infected individuals are at increased risk of neurocognitive impairment compared to the general population. Studies suggest that, despite combination antiretroviral therapy (cART), HIV infection causes immune activation which results in neural damage; however, few data exist in HIV-infected youth. Methods HIV-infected youth 8–26 years old on cART with virologic suppression were prospectively enrolled along with healthy controls. Neurocognitive performance was assessed by age-appropriate Wechsler Intelligence Scales. Soluble and cellular markers of T-lymphocyte and monocyte activation were measured by ELISA and flow cytometry, respectively. Results 45 HIV-infected subjects and 21 controls were enrolled. Markers of T-cell and monocyte activation were higher in the HIV-infected subjects compared to controls, but proportions of inflammatory and patrolling monocytes were similar. Although there was no significant differences in neurocognitive scores between the HIV-infected and control groups, scores were low-average for 4 of 5 testing domains for the HIV-infected subjects and average for all 5 in the controls, and % of HIV-infected subjects with scores classified as “low average” or below was higher than in the controls. Variables most associated with neurocognitive performance among HIV-infected subjects included activated CD4+ T-cells (% CD4+CD38+HLA-DR), monocyte activation (soluble CD14), HIV duration, age and sex. Conclusions HIV-infected youth on cART with virologic suppression show subtle evidence of neurocognitive impairment compared to healthy controls, and increased immune activation appears to play a role. Additional studies are needed to develop strategic interventions beyond cART to potentially improve neurocognitive performance and/or minimize further impairment in this vulnerable population.

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Cannabinoid Neuroimmune Modulation of SIV Disease

Cited by 53 publications

References 80 publications

Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model

Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

Neurocognitive Dysfunction in HIV-Infected Youth: Investigating the Relationship with Immune Activation

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