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Cannabinoids, the active ingredient in marijuana, and their derivatives have received remarkable attention in the last two decades because they can affect tumor growth and metastasis. There is a large body of evidence from in vivo and in vitro models showing that cannabinoids and their receptors influence the immune system, viral pathogenesis, and viral replication. The present study reviews current insights into the role of cannabinoids and their receptors on viral infections. The results reported here indicate that cannabinoids and their receptors have different sequels for viral infection. Although activation or inhibition of cannabinoid receptors in the majority of viral infections are proper targets for development of safe and effective treatments, caution is required before using pharmaceutical cannabinoids as a treatment agent for patients with viral infections. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Journal of Medical Virology
Effects of Cannabinoids and their Receptors on
Viral Infections
Alireza Tahamtan,
Masoumeh Tavakoli-Yaraki,
Tomasz P. Rygiel,
Talat Mokhtari-Azad,
and Vahid Salimi
Departmentof Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
Department of Immunology, Medical University of Warsaw, Center of Biostructure Research, Warsaw, Poland
Cannabinoids, the active ingredient in mari-
juana, and their derivatives have received
remarkable attention in the last two decades
because they can affect tumor growth and
metastasis. There is a large body of evidence
from in vivo and in vitro models showing that
cannabinoids and their receptors influence the
immune system, viral pathogenesis, and viral
replication. The present study reviews current
insights into the role of cannabinoids and their
receptors on viral infections. The results
reported here indicate that cannabinoids and
their receptors have different sequels for viral
infection. Although activation or inhibition of
cannabinoid receptors in the majority of viral
infections are proper targets for development
of safe and effective treatments, caution is
required before using pharmaceutical cannabi-
noids as a treatment agent for patients with
viral infections. J. Med. Virol. ©2015 Wiley
Periodicals, Inc.
KEY WORDS: cannabinoid receptors; viral in-
fections; marijuana; immuno-
modulation; anti-inflammation
Cannabinoids are a pharmacological class of natu-
ral compounds found in the marijuana hemp plant
and chemically related synthetic products. This in-
cludes a variety of endogenous and exogenous/syn-
thetic components that exhibit similar
pharmacological properties. Cannabinoids have been
used for centuries, but their major psychoactive
component, D9-tetrahydrocannabinol (D9-THC), was
only identified in the second half of the 20th century
[Fine and Rosenfeld, 2013].
The medical therapeutic potential of cannabinoids
has been demonstrated in preclinical and clinical
studies [Smith et al., 2010; Fine and Rosenfeld,
2013]. The biological and therapeutic activity of
cannabinoids is mediated by cannabinoid receptors
(CB1 and CB2) through activation of heterotrimeric
G-proteins. G-proteins act as adaptors that link G-
protein-coupled receptors (GPCRs) to other signaling
and regulatory proteins to operate or modulate intra-
cellular signaling pathways [Smith et al., 2010].
Both endogenous and exogenous cannabinoids
can activate cannabinoid receptors. CB1 and CB2
receptors structurally similar, but their genes are
located on different chromosomes (chromosome 6 and
1 in humans, respectively), and they have different
tissue distributions and physiological properties
[Hulsebosch, 2012]. The psychoactive function of
cannabinoids are mediated by CB1; CB2 receptors
Abbreviations::D9-THC, D9tetrahydrocannabinol,; CB, canna-
binoid receptors; GPCRs, G-protein-coupled receptors; CNS,
central nerves system; MAPK, mitogen activated protein kinases;
ERK, extracellular signal-regulated kinases; JNKs, c-Jun N-
terminal kinases; Rac, ras-related C3 botulinum toxin substrate;
Cdc, cell division control protein; HCV, hepatitis C virus; CHC,
chronic hepatitis C; HIV, human immunodeficiency virus; Pol,
polymerase; LTR, long terminal repeat; RT, reverse transcrip-
tase; Tat, transactivator; BBB, blood brain barrier; HBMEC,
human brain microvascular endothelial cells; CTL, cytotoxic T
lymphocyte; CXCR4, C-X-C chemokine receptor type 4; SDF1,
stromal cell-derived factor 1; CXCL12, C-X-C chemokine ligand
type 12; CCR5, C-C chemokine receptor type; VCAM-1, vascular
cell adhesion molecule 1; ORF, open reading frame; HSV, human
herpes viruses; TMEV, theiler’s murine encephalomyelitis virus;
MS, multiple sclerosis; CSF, cerebrospinal fluid; VSV, vesicular
stomatitis virus; KSHV, kaposi’s sarcoma-associated herpesvirus;
HHV, human herpesviruse; FeLV, feline leukemia virus; BDV,
borna disease virus; SIV, simian immunodeficiency virus
Grant sponsor: School of Public Health, ; Grant sponsor:
Tehran University of Medical Sciences; Grant number: 92-03-27-
Conflicts of interest: None.
Correspondence to: Vahid Salimi, PhD, Department of
Virology, School of Public Health, Tehran University of Medical
Sciences, Enghelab St, Ghods St, Poorsina Ave, Tehran, Iran. P.O.
Box 6446, Tehran 14155, Iran.
Accepted 1 June 2015
DOI 10.1002/jmv.24292
Published online in Wiley Online Library
involve inflammatory and immunomodulatory
processes [Miller and Stella, 2008].
CB1 receptor is abundantly expressed in the
central nerves system (CNS), particularly in the
neocortex, hippocampus, basal ganglia, and cerebel-
lum. It is also present in the lung, liver, and kidney,
where it functions as a GPCR. In vivo investigations
have confirmed that the psychoactive and neuro-
protective properties of cannabinoids are mediated
through the activation of CB1 receptors (Table I).
The pharmacological targeting of CB1 is a promising
treatment for multiple CNS disorders [Smith et al.,
The CB2 receptor is predominantly expressed in
the immune and immune-derived cells (B and T
lymphocytes, natural killer cells, monocytes, neutro-
phils, etc.), as well as in peripheral tissues such as
the liver [Yao and Mackie, 2009]. The CB2 receptor
regulates mitogen-activated protein kinase (MAPK)
pathways (ERK, JNK and p38). Depending on the
cell type and cell differentiation state, MAPK signal-
ing can be stimulated or inhibited. Part of MAPK
CB2 regulates other signaling pathways, including
the stimulation of phospholipase C and A2, and small
GTPases Rho, Rac, and Cdc42 [Rom and Persidsky,
The anti-inflammatory and immunomodulatory
properties of CB2 receptors have been investigated in
in vitro and in vivo studies where CB2 receptors
interact with signaling pathways, enzymes, and fac-
tors involved in modulation of the immune system
(Table II). Overall activation of the CB2 receptor can
cause apoptosis, suppression of cell proliferation,
inhibition of pro-inflammatory cytokine/chemokine
production, and induction of anti-inflammatory
cytokines and regulatory T cells [Rieder et al., 2010;
Chandra et al., 2014].
Activated CB2 receptors play a significant role in
leukocyte and endothelial migration, activation, and
interaction, which is related to the anti-inflammatory
and immunomodulatory effects of CB2 [Rom and
Persidsky, 2013]. Activated receptors inhibit the
migration of chemokine-induced monocytes by down-
regulation of their receptors and suppression of
(IFNg)-induced ICAM-1 expression [Miller and Stella,
2008]. CB2 receptors suppress chemokine-induced
chemotaxis of neutrophils, lymphocytes,
macrophages, monocytes, and microglia by inhibiting
leukocyte migration mediated by RhoA activation
[Kurihara et al., 2006; Miller and Stella, 2008], and
affects dendritic cell migration by inhibiting matrix
metalloproteinase-9 expression [Adhikary et al.,
2012]. In addition, CB2 activation in human leuko-
cytes suppresses adhesion and engagement with the
brain endothelium by decreasing the expression of
the adhesion molecules needed for this interaction. It
also decreases leukocyte migration across the endo-
thelial, thus suppressing inflammatory leukocyte
responses and preventing blood brain barrier (BBB)
injury and permeability in neuroinflammation [Rom
et al., 2013; Ramirez et al., 2012]. The cannabinoid
system can modulate inflammatory activation of the
endothelium [Wilhelmsen et al., 2014], and reduce
TNFa-induced activation of the human coronary
artery endothelium and secretion of MCP-1 and
attenuated monocyte transendothelial migration [Ra-
jesh et al., 2007].
The effects of cannabinoids and their receptors
(CB1, CB2) on viral infections have been studied. The
CB1 receptor is abundantly expressed in CNS and its
activation could strongly affect the ability of a viral
infection in neuronal tissue [Herrera et al., 2008].
Induction of CB1 receptors during viral infections in
neuronal cells could activate the MAPK cascade,
TABLE I. CB1 Receptor Activation
Effects Causes Ref
Inhibits adenylate cyclase activity Decrease activity of protein kinase A Howlett et al. [1986]
Inhibits N and P/Q types Ca
channels Modulation of synaptic transmission at
CNS synapses
Pan et al. [1996];
Twitchell et al. [1997]
Activation of p42/p44 MAPK Leads to the expression of the growth
related gene Krox-24
Bouaboula et al. [1995]
Stimulates inward rectifying K
(GIRK) channels Play a major role in determining
neuronal excitability
Mackie et al. [1995]
Inhibits Na
channels Depress synaptic transmission in brain Nicholson et al. [2003]
Stimulates phospholipases C and A2 Control phospholipid metabolism Hunter et al. [1986]
Activates ceramide signaling pathway in astrocytes
via direct interaction with FAN
Sphingomyelin hydrolysis Smith et al. [2010]
Activates c-Jun N-terminal (JNK) and p38 kinases Regulation of neurogenesis Rueda et al. [2002]
Attenuates Rap1/B-Raf/ ERK pathway Inhibits neuronal progenitor cell
Rueda et al. [2002]
Diminishes excitotoxicity in postsynaptic neurons Induced protective mechanisms Marsicano et al. [2003]
Enhances vasodilation in vascular smooth muscle
and inhibites endothelin-1
Exerts vascular effects such as
vasodilatation and hypotension
Ronco et al. [2007]
Decreases the release of pro-inflammatory mediators
including NO and TNFa
Neuroprotective effect Fernandez-Lopez et al.
Modulates dopamine release in the
mesocorticolimbic system
Involved in the drug addiction Maldonado et al. [2006]
J. Med. Virol. DOI 10.1002/jmv
2 Tahamtan et al.
phosphorylate ERK, and decrease cellular Ca
concentrations. This would impair Ca
enzymes, pro-inflammatory mediators, NOS-1 activ-
ity, and NO production, which are essential for
development of host responses to viral infections and
suppress anti-viral responses [Herrera et al., 2008;
Reiss, 2010; Liu, 2009]. Beside the therapeutic and
neuroprotective character of CB1 receptor activation
in neuronal cells in response to neuroinflammatory or
neurodegenerative disease [Rom and Persidsky,
2013], activation of these receptors could have impor-
tant implications for the pathogenesis of viruses
affecting the CNS. These include HHV, HIV, VSV,
BDV, measles, mumps, rabies, enteroviruses, La
Crosse encephalitis, lymphocytic choriomeningitis, St.
Louis encephalitis, West Nile, California encephalitis,
etc. In addition, CB1 receptors expression in cells of
the lung and liver may directly or indirectly affect
viral infections [Rice et al., 1997; Van der Poorten
et al., 2010].
The CB2 receptor is abundantly expressed in
immune and immune-derived cells and its activation
indirectly affects viral infections by altering host
immune responses, particularly inflammation, along
different signaling pathways (Table II). Inflamma-
tion is critical for the control of viral infection
through recruitment of innate and adaptive immune
cells [Klein and Cabral, 2006]. The anti-inflamma-
tory and immunomodulatory activity of CB2 signal-
ing can suppress inflammation and modulate
development of immune responses to viral infections
[Kaminski, 1996; Correa et al., 2005; Rom and
Persidsky, 2013]. In most cases, activation of canna-
binoid receptors increases the progression of a viral
disease by modulation of the immune response
[Reiss, 2010]. In these viral infections, blockage of
CB2 receptors is potential target for control of viral
infection through inhibition of immune suppressive
effects (Table,I I).
Inflammation also contributes to the pathology of
viruses such as influenza, respiratory syncytial virus
(RSV), hepatitis B virus (HBV), and Borna disease
virus (BDV). In viral infections where the host
inflammatory response is pathogenic (immunopatho-
genic), activation of receptors is beneficial for control
of the development, progression, and pathology of
the viral disease [Reiss, 2010] (Fig. 1). This is
general information about the effects of cannabinoid
immunomodulation on viral infections; it is not
universal and studies on the subject have conflicting
results [Molina et al., 2011b]. The present study
summarizes the effects and possible mechanisms of
cannabinoids and their receptors on viral infections
(Table III).
TABLE II. CB2 Receptor Activation
Effects Causes Ref
Inhibits adenylate cyclase activity Decrease activity of protein
kinase A
Howlett et al.
Induces phosphorylation of p44/42 MAPK and PKB/Akt
via PI3K pathway
Neuroprotective effect Offertaler et al.
Reduces Erk1/2 and JNK1/2 activation Anti-inflammatory effect Gertsch et al.
Activation of phospholipases C Leading to release Ca
Shoemaker et al.
Regulates small G proteins such as Rho, Rac, Cdc42 Suppress neutrophil migration Kurihara et al.
Activates JNK via the PI3K/Akt pathway Neuroprotective effect Viscomi et al.
Decreases CXCR4-activation mediated G-protein activity and
alters cytoskeletal reorganization
Inhibit actin reorganization
and impair productive infection
Costantino et al.
Triggers apoptosis in immune cells Immunosuppressive effect Rom and Persidsky
Inhibits the release of neurotoxic factors and suppress
microglia activation
Anti-inflammatory effect Klegeris et al.
Preventes neuronal injury during neuroinflammation via
upregulation of MAPK phosphatase-1(MKP-1)
Protects neurons from
inflammatory damage
et al. [2006]
Reduces iNOS production via inhibition of ERK-1/2
phosphorylation in microglia during inflammation
Anti-inflammatory effect Merighi et al.
Decreases the release of pro-inflammatory mediators
including NO and TNFa
Neuroprotective effect Fernandez-Lopez
et al. [2006]
Reduces the chemotaxis and adherence of neutrophils to brain
endothelial by activating p38
Protects against ischemic
brain injury
Murikinati et al.
Negatively regulates IL-12p40 production in macrophages and
increase IL-10 production
Anti-inflammatory effect Correa et al. [2005]
Suppresses TNFaand IL-1bproduction in monocytes Anti-inflammatory effect Gertsch et al.
Inhibits LPS-induced NF-kB activation Anti-inflammatory effect Louvet et al. [2011]
Enhances release of the anti-inflammatory factors, IL-4
and IL-10
Anti-inflammatory effect Molina-Holgado
et al. [1998]
J. Med. Virol. DOI 10.1002/jmv
The Cannabinoids and Viral Infection 3
The influenza virus is a common respiratory
pathogen that infects the epithelium of airways. The
viral infection infiltrates immune cells in the pulmo-
nary airways. Because the normal anti-viral response
of the infiltrating immune cells is directed against
infected epithelial cells, the anti-viral response may
cause immunopathogenesis [Ronni et al., 1995; Bot
et al., 1996]. Several studies have evaluated the
effects of CB receptor activation on the immune
response to the influenza virus and the resulting
infection [Karmaus et al., 2013].
Signaling by CB1 and CB2 receptors modulate
immune responses; the lack of CB1 and CB2 recep-
tors could increase inflammation and tissue damage
after infection with influenza [Karmaus et al., 2011].
The treatment of mice with D9-THC, a CB1, and CB2
receptors agonist, decreased recruitment of immune
cells, especially monocytes, and lymphocytes, to the
pulmonary airway. Although the stimulation of both
CB receptors decreased the immunopathology of the
virus, it increased the viral load as well [Buchweitz
et al., 2007]. The D9-THC-suppressed responses of
dendritic, macrophage, and myeloid cells by CB1 and
CB2 receptor signaling could impair the inflamma-
tory response to influenza [Karmaus et al., 2013]. It
was determined that D9-THC could modulate
immune responses against the influenza virus
through CB receptors independent manners [Buch-
weitz et al., 2008; Karmaus et al., 2011].
These results suggest that CB receptor activation
can impair immune responses induced by influenza.
This could help control viral immunopathology in
severe cases; however recovery from influenza would
be delayed and caution is required before using
pharmaceutical cannabinoids.
Hepatitis C
Hepatitis C virus (HCV) infects approximately 170
million people worldwide and is a leading cause of
liver diseases such as fibrosis, cirrhosis, and cancer
[Poynard et al., 2003]. Several studies have suggested
that activation of CB receptors could play an impor-
tant role in the development and progression of HCV
[Coppola et al., 2014a,b]. CB1 and CB2 receptors are
expressed at low levels in normal liver tissue, but are
highly expressed in liver disorders such as HCV [Van
der Poorten et al., 2010]. HCV activates CB1
receptors and these activated receptors appear to
contribute to liver steatosis, fibrogenesis, and cirrho-
sis through cannabinoid signaling pathways [Sun
et al., 2014]. In contrast, activation of CB2 receptors
appears to exert hepatoprotective and anti-fibroge-
netic effects [Toyoda et al., 2011]. Signaling via CB1
receptors up-regulates the gluconeogenic and
lipogenic transcription factors that lead to hepatic
glucose disorders and dyslipidemia [Toyoda et al.,
2011; Sun et al., 2014]. These disorders in chronic
hepatitis C (CHC) are associated with liver fibro-
genesis, the risk factor of higher levels of HCV
replication, and liver cancer [Van der Poorten et al.,
2010; Sun et al., 2014].
The CB2 receptor variants have been shown to be
affected differently by HCV. The literature suggests
that the CB2-63 QQ variant is associated with more
severe liver disease in patients with CHC. Patients
with the QQ variant have higher serum levels of
aminotransferase and histologic activity index scores
than those with other variants. Moreover, moderate
or severe CHC has been identified more frequently in
patients with the QQ variant [Coppola et al., 2014a].
The association between QQ variant and severe liver
disease in CHC may be the result of the increased
Figure 1. Effect of cannabinoid receptor activation on viral infections. Activation of CB1 and
CB2 receptors inhibits the production of pro-inflammatory mediator. CB1 receptors inhibit Ca
channels and CB2 receptors induce anti-inflammatory factors, inhibiting inflammation. Inflam-
mation is essential to suppress viral disease progression on the one hand and, on the other, is
involved in (immune) pathogenesis of several viral infections. Activation of CB1 and CB2
receptors increase progression of viral diseases and/or inhibit viral immune pathogenesis.
J. Med. Virol. DOI 10.1002/jmv
4 Tahamtan et al.
TABLE III. Cannabinoids Effect on Viral Infections
Viral infection Results Ref
D9-THC suppress DC, Mac/MФand inflammatory myeloid cell responses, in a
mechanism involving CB1 and/or CB2 receptors activation
Karmaus et al.
Deletion of CB1 and CB2 receptors exacerbates APC function to increase
inflammation and cellular immunity during influenza infection
Karmaus et al.
D9-THC modulate immunological and pulmonary airway responses to influenza virus
through CB receptors dependent and independent mechanisms
Buchweitz et al.
D9-THC increase viral load, decreasse recruitment of CD4 and CD8 T lymphocytes,
decreasse airway epithelial cell apoptosis and mucous cell metaplasia
Buchweitz et al.
HCV The CB2 polymorphism (CB2-63 QQ variant) associate with more severe
inflammation and hepatocellular necrosis in patients with HCV infection
Coppola et al.
The CB2 polymorphism (CB2-63 QQ variant) independently associate with
persistently normal aminotransferase serum levels in chronic HCV
Coppola et al.
CB receptors activation contributes to glucose metabolism disorders of hepatocytes
and promotes HCV replication
Sun et al. [2014]
HCV infection may activate the cannabinoid system and precede steatosis, but the
core protein by itself may not have any effect on the cannabinoid system
Toyoda et al. [2011]
CB1 receptor is up-regulated in chronic HCV patient and is associate with increase
steatosis in genotype 3
Van der Poorten
et al. [2010]
Cannabis may be beneficial by alleviating common side effects associated with
interferon ribavirin, including anorexia, nausea, weight loss and insomnia
Costiniuk et al.
Daily cannabis use is strongly associate with fibrosis and that HCV-infected
individuals should be counseled to reduce or abstain from cannabis use
Ishida et al. [2008]
Daily cannabis smoking is significantly associate with fibrosis progression during
chronic HCV
ezode et al. [2005]
HIV Cannabinoid receptors activation inhibits HIV-1 Tat-stimulated adhesion of human
monocyte-like cells to extracellular matrix proteins
Raborn et al. [2014]
Synthetic cannabinoids are capable of protecting human dopaminergic neurons from
HIV-1 gp120 damages
Hu et al. [2013]
CB2 receptors activation partially inhibite the HIV-1 pol expression, RT activity and
LTR activation in macrophages
Ramirez et al.
D9-THC suppress/enhance CD8 T cell proliferation and HIV-1 gp120 CTL response Chen et al. [2012]
CB2 activation mediate in attenuation of CXCR4-tropic HIV infection in primary
T cells
Costantino et al.
Cannabinoid receptors activation are able to modulate appetite hormones in
HIV-infected patients
Riggs et al. [2012]
Prenatal exposure to D9-THC triggers profound T cell dysfunction Lombard et al.
Cannabinoids using prevent the impairment of network function produced by HIV-1
Kim et al. [2011]
CB inhibit migration of microglial-like cells to the HIV-Tat Fraga et al. [2011]
Cannabinoid mediate modulation of macrophage migration to the HIV-1 Tat protein
is linked to the CB2 receptors
Raborn and Cabral
Elevated levels of SDF-1a/CXCL12 in the brain diminish the thermoregulatory
response of cannabinoids
Benamar et al.
CB1 are able to restore the integrity of brain microvascular endothelial cells and the
BBB following insults by Gp120
Lu et al. [2008]
CB2 receptors are involved in WIN55,212-2’s mediated inhibition of HIV-1 expression
in microglial cells
Rock et al. [2007]
D9-THC suppress immune function, increase HIV coreceptor and act as a cofactor to
enhance HIV replication
Roth et al. [2005]
WIN 55,212-2 inhibit HIV-1 expression in a concentration and time dependent
manner in CD4
T and microglial cells
Petersona et al.
Cannabinoids alter HIV RNA levels by immune modulation or cannabinoid-protease
inhibitor interactions
Abrams et al.
The CB activation reduce theTat induced cytotoxicity, by the modulation of the
L-arginine/NO pathway
Esposito et al.
HHV The CB1/CB2 receptors agonist WIN-55,212-2 have antimitogenic effects on Kaposi’s
sarcoma cells
Luca et al. [2009]
D9-THC increase viral load in KSHV infected cells, stimulate expression of the KSHV
encoded viral G protein coupled receptor and Kaposi’s sarcoma cell proliferation
Zhang et al. [2007]
D9-THC inhibits lytic replication of gamma oncogenic HHV in vitro, through
inhibition of the ORF 50 promoter
Medveczky et al.
D9-THC elicits dysfunction in CTL by altering effector cell-target cell postconjugation
et al. [1992]
D9-THC suppresses macrophage extrinsic anti-HHV activity Cabral and
Vasquez [1991]
D9-THC inhibits immune responsiveness of B6C3F1 mice to homotypic challenge
with HSV-2
Cabral et al. [1987]
J. Med. Virol. DOI 10.1002/jmv
The Cannabinoids and Viral Infection 5
inhibition of T cells when QQ variants are activated,
which then produces a less active immune response
to HCV. QQ variants are increase HCV replication
and allow the virus to induce liver disease [Coppola
et al., 2014a]. It has been demonstrated that QQ
variants are associated with persistently normal
aminotransferase serum levels in CHC. Association of
QQ variants and persistently normal aminotransfer-
ase serum levels in CHC could result from robust
inhibition of the T cells with QQ variants activation
and the subsequent less active immune response to
infected hepatic cells [Coppola et al., 2014b].
These results suggest that CB1 receptor activation
may contribute to liver disorders in HCV infection,
but that CB2 receptors produce different effects
according to their variant.
Human immunodeficiency virus (HIV) causes ac-
quired immunodeficiency syndrome, a leading cause
of death worldwide [Wang and Ho, 2011]. It has been
suggested that drug use, such as the use of cannabis,
plays a role in the development and progression of
HIV by its immunomodulatory and neuromodulatory
effects. Studies have examined the function of canna-
binoids and their receptors in HIV replication,
pathogenesis, and immuneregulation [Gurwitz and
Kloog, 1998; Wang and Ho, 2011; Riggs et al., 2012].
The endocannabinoid system also has an important
connection to HIV-associated dementia [Bari et al.,
Activation of cannabinoid receptors can modulate
tissue inflammation and reduce neurological compli-
cations; thus, targeting of cannabinoid receptors,
specifically CB1, has been suggested as a potential
treatment for HIV-1 associated neuropathic disorders
[Woolridge et al., 2005; Abrams et al., 2007; Ellis
et al., 2009; Chen et al., 2012]. The breakdown of the
BBB and human brain microvascular endothelial
cells (HBMEC) occurs in HIV associated neurodege-
nerative diseases. Activated CB1 receptors can return
to the primary condition of the BBB and HBMEC
following insults by HIV-1 Gp120 [Lu et al., 2008].
CB1 receptor activation reduces HIV-1 Tat-induced
cytotoxicity by modulation of the L-arginine/NO path-
way and is itself regulated by HIV-1 Tat [Esposito
et al., 2002].
HIV can up-regulate CB2 signaling pathways by
up-regulation of CB2 receptor. Up-regulation of CB2
receptors have been detected in microglia, astrocytes,
and perivascular macrophages in HIV-1 associated
encephalitis [Cosenza-Nashat et al., 2011]. Up-regu-
lation of CB2 receptors has also been shown in
differentiated macrophages promoted by HIV. Acti-
vated CB2 receptors have different effects on HIV
infection; they inhibit HIV-1 polymerase (Pol) expres-
sion and decrease HIV-1 reverse transcriptase (RT)
activity, activate long terminal repeat (LTR) in
infected macrophages [Ramirez et al., 2013], and
inhibit HIV-1 expression in microglia and CD4
lymphocytes [Petersona et al., 2004; Rock et al.,
2007]. They suppress HIV-1 Tat IFN-g-induced and
NO-mediated cell toxicity in glioma cells [Esposito
et al., 2002], diminish macrophages, and microglial-
like cell migration in response to HIV-1 Tat [Raborn
and Cabral, 2010; Fraga et al., 2011], and decrease
HIV-1 co-receptor CXCR4 activation mediated by G-
protein activity and MAPK phosphorylation [Costan-
tino et al., 2012]. Furthermore, CB2 receptor activa-
tion protects human dopaminergic neurons from
gp120 damage [Hu et al., 2013], prevents the impair-
ment of network function produced by HIV-1 gp120
[Kim et al., 2011], and suppresses HIV-1 Tat-stimu-
lated adhesion of human monocyte-like cells to ex-
tracellular matrix proteins [Raborn et al., 2014].
TABLE III. (Continued)
Viral infection Results Ref
D9-THC decreases alpha/beta interferon response to herpes simplex virus type 2 in
the B6C3F1 mouse
Cabral et al. [1986]
D9-THC enhances the release of HSV-2 by perturbing cellular membranes in
virus-infected cells
Cabral et al. [1986]
D9-THC decreases host resistance to HSV-2 vaginal infection Mishkin and Cabral
D9-THC enhance severity and duration of symptoms in vaccinia virus infected mice Huemer et al.
Cannabinoids abusing interfere with antibody response after a generalised
orthopoxvirus infection
Huemer et al.
Cannabinoid rescue of striatal progenitor cells in chronic Borna disease viral
encephalitis in rats
Solbrig et al. [2008]
D9-THC administration decrease morbidity and mortality of SIV infected macaques Molina et al. [2011]
CB1 activation may contribute to decreased inflammation and increased VSV
replication in neurons
Molina et al. [2011]
Chronic D9-THC administration increases lymphocyte CXCR4 expression in rhesus
LeCapitaine et al.
Cannabinoid inhibits TMEV induced VCAM-1 and reduces leukocyte transmigration
by activation of CB1 receptors
Mestre et al. [2011]
CB activation reduces inflammation, returns motor coordination, induces
remyelination in TMEV infected mice
Arvalo-Martın et al.
J. Med. Virol. DOI 10.1002/jmv
6 Tahamtan et al.
Cannabinoids could alter the RNA levels of HIV by
immune modulation and interaction with protease
inhibitors [Abrams et al., 2003]; however, prenatal
exposure to cannabinoids seriously affects the im-
mune response in neonatal and postnatal life and
could influence susceptibility to HIV [Lombard et al.,
2011]. A hybrid mouse model (huPBL-SCID) was
used to demonstrate that cannabinoids can modulate
immune function, increase HIV co-receptor expres-
sion, and be a cofactor role for HIV replication [Roth
et al., 2005]. Elevated levels of SDF-1a/CXCL12 as
CXCR4 ligands in the brain reduce the thermoreg-
ulatory response to cannabinoids. There is physiolog-
ical evidence for a thermoregulatory interaction
between HIV-1 co-receptor CXCR4 and the cannabi-
noid system in the brain [Benamar et al., 2009].
Chronic administration of D9-THC ameliorates the
progression of simian immunodeficiency virus (SIV)
disease [animal model of HIV], attenuates inflamma-
tion and plasma/CSF viral load, modulates gut-spe-
cific mechanisms, and decreases morbidity and
mortality of SIV infected macaques [Molina et al.,
2011a,b, 2014]. Moreover, prolonged D9-THC admin-
istration increases T lymphocyte CXCR4 expression
on both CD4
and CD8
T lymphocytes [LeCapitaine
et al., 2011], and induces intestinal anti-inflamma-
tory miRNA expression profile during acute SIV
infection of rhesus macaques [Chandra et al., 2014].
Additionally, the incidence of significant neuropatho-
logy and opportunistic infections was lower in
SIV-infected subjects chronically treated with D9-
THC compared to control subjects [Winsauer,
2011]. It has been shown that expression of CB2
receptors in the brain of macaques was induced
during SIV encephalitis, specifically in perivascular
macrophages, microglial nodules, and infiltrated
lymphocytes. Because activated CB2 receptors are
associated with reduced antiviral response of these
cells, it could favor the entry of infected cells to CNS
and suggests that the endocannabinoid system may
contribute to the development of HIV-induced ence-
phalitis [Benito et al., 2005].
This data indicates that cannabinoids and their
receptors (CB1 and CB2) have significant effects on
HIV pathogenesis and immune regulation. During
viral entry cannabinoids effect HIV-1 co-receptor
expression [LeCapitaine et al., 2011; Roth et al.,
2005; Costantino et al., 2012], during replication
effect several HIV enzymes [Ramirez et al., 2013], in
pathogenesis effect HIV cytotoxic proteins [Esposito
et al., 2002; Kim et al., 2011; Hu et al., 2013], and
importantly, alter HIV RNA levels by immune
modulation [Abrams et al., 2003]. The exact mecha-
nisms underlying these functions remain unclear and
require further investigation.
Herpes Simplex
Herpes simplex viruses (HSVs) are a large family
of DNA viruses that cause oral and genital lesions,
encephalitis, neonatal infections, and tumors in
humans. Cannabinoids are immunosuppressant and
effect replication of HSV latency and pathogenesis
[Medveczky et al., 2004].
An in vitro study demonstrated that cannabinoids
significantly cause malfunction of cytotoxic T lympho-
cytes (CTLs) by targeting post conjugation of CTL
cells. Treatment of HSV-1 infected cells with D9-THC
inhibits the activity of CTL against infected cells
[Fischer-Stenger et al., 1992]. Furthermore, D9-THC
can suppress macrophage extrinsic anti-HSV function
[Cabral and Vasquez, 1991]. It has been shown that
D9-THC suppresses the splenocyte proliferative
response to HSV-2 and enhances the release of HSV-
2 by disturbing cellular membranes in virus infected
cells [Cabral et al., 1986a,1987a]. D9-THC reduces
host resistance to HSV-2 vaginal infection by sup-
pression of the immune response to primary infection
by HSV-2 [Mishkin and Cabral, 1985; Cabral et al.,
D9-THC has been also shown to suppress reactiva-
tion and lytic replication of gamma oncogenic herpes
viruses in vitro by inhibition of viral and cellular
mechanisms required for replication and open
reading frame 50 promoter (ORF 50) [Medveczky
et al., 2004]. There is evidence to show that, for
Kaposi’s sarcoma, cannabinoids act as a cofactor by
elevating virus replication and infection by activation
of the virus lytic switch gene and stimulating the
Kaposi’s sarcoma virus associated endothelial
transformation [Zhang et al., 2007].
This data demonstrates that cannabinoids have
different effects on HSV replication, latency, and
pathogenesis by immune suppression and interaction
with several viral genes and cellular mechanisms
[Medveczky et al., 2004; Zhang et al., 2007].
Other Viruses
Cannabinoids also effect infection by other viruses.
Recreational cannabinoid use has been found to
interfere with antibody production after a generalized
orthopoxvirus infection [Huemer et al., 2007].
Furthermore, cannabinoids increase the virulence of
the vaccinia virus by immune modulation [Huemer
et al., 2011]. Cannabinoids are promising therapies
in neuroinflammatory and neurodegenerative
disorders to control CNS inflammation by reducing
microglia activation [Solbrig et al., 2013]. Given its
neuroprotective roles, cannabinoid treatment protect
striatal progenitor cells in chronic BDV encephalitis
in rats [Solbrig and Hermanowicz, 2008].
It has been detected in Theiler’s murine encephalo-
myelitis virus (TMEV) models for multiple sclerosis
that activation of cannabinoid receptors inhibits
brain VCAM-1 expression and reduced leukocyte
transmigration [Mestre et al., 2011]. In addition,
receptors activation reduces inflammation, returns
motor coordination, induces remyelination and poten-
tiates interleukin-6 production in TMEV infected
J. Med. Virol. DOI 10.1002/jmv
The Cannabinoids and Viral Infection 7
mice [Molina-Holgado et al., 1998; Arvalo-Martın
et al., 2003]. Activation of CB1 receptors blocks anti-
viral responses to vesicular stomatitis virus (VSV)
and thus enhances viral replication in neurons
[Herrera et al., 2008].
Viruses and Cannabinoids: A Double-Edged
In the last two decades, cannabinoids and their
derivatives have been shown to effect tumor growth
and metastasis. There is a large body of evidence
from in vivo and in vitro models showing that
cannabinoids and their receptors effect the immune
system, viral pathogenesis, and viral replication.
The CB1/CB2 receptors are attractive pharmaceut-
ical targets for the design of safe and effective
treatments because of their beneficial biological prop-
erties and therapeutic potential [Smith et al., 2010;
Fine and Rosenfeld, 2013]. The cloning of CB1 and
CB2 receptors in the early 1990’s led to development
of selective CB1 and CB2 receptor agonists and
antagonists for use as treatment agents [Pertwee
et al,. 2000]; however, major practical difficulties
were encountered in experiments with CB ligands
[Pertwee et al., 2000].
The reports reviewed in this study indicate that
cannabinoids and their receptors have significant
effects on viral infection, but the exact mechanisms
underlying these functions remain unclear. Identifi-
cation of the mechanisms responsible for these func-
tions is complicated because of the multiplicity of
cannabinoid-related signaling and effects [Smith
et al., 2010; Rom and Persidsky, 2013], tissue-specific
responses to the viral infection [Lee et al., 2007;
Zaritsky et al., 2013], multiple cellular mechanisms
involved in inflammatory responses [Klein and
Cabral, 2006], and kinetics of viral replication
[Molina et al., 2011b]. Evidence suggests that canna-
binoids may systematically influence viral infection
through regulation of host immunity and inflamma-
tory response [Reiss, 2010; Rom and Persidsky,
2013], cell metabolism [Molina et al., 2011b], and the
ability to enter host cells [Benamar et al., 2009],
integrate into the host genome [Valk, 1997,1999],
replicate [Roth et al., 2005; Rock et al., 2007; Molina
et al., 2014], be released [Cabral et al., 1986], and by
novel epigenomic and miRNA regulatory mechanisms
[D’Addario et al., 2013; Paradisi et al., 2008; Chandra
et al., 2014]. The exact molecular mechanisms
underlying the effects of cannabinoids remain unad-
dressed, but these effects can be explained by the CB
receptor signaling pathways and their inhibitory and
stimulatory effects.
In immunomodulation of cannabinoids in viral
infections where viral replication is sensitive to the
anti-viral responses, activation of CB receptors in-
creases progression of the disease by inhibition of
immune anti-viral responses. For example; viral
infection by orthopoxvirus [Huemer et al., 2007],
vaccinia [Huemer et al., 2011], HCV [Sun et al.,
2014], HSV-1 [Fischer-Stenger et al., 1992], HSV-2
[Cabral et al., 1987], Kaposi’s sarcoma-associated
herpes virus [Zhang et al., 2007], HIV, and feline
leukemia [Wang and Ho, 2011] increases during CB
receptor activation.
Contradictions exist in the literature about the
effects of cannabinoids on viral infections. For exam-
ple, in HIV, viral replication is enhanced in an
inflammatory state and chronic inflammatory condi-
tions are related to an increased level of viremia
[Kfutwah et al., 2006; Groot et al., 2006]; thus, CB
activation could suppress viral replication by anti-
inflammatory action [Molina et al., 2011b]. In vitro
studies have shown that WIN 55,212-2 strongly
inhibits HIV-1 expression in microglial [Rock et al.,
2007; Peterson et al., 2004], CD4
[Peterson et al., 2004], and macrophage cell cultures
through CB2 receptors [Ramirez et al., 2013].
Involvement of CB2 receptors in cannabinoid anti-
viral activity suggests that cannabinoid receptor
agonists directly suppress viral replication [Rock
et al., 2007; Molina et al., 2011b].
Evidence primarily from in vitro studies indicates
that cannabinoids enhance HIV-1 infection of suscep-
tible cells. For example, increased syncytia formation
when MT-2 cells were cultured in the presence of
cannabinoid agonists and HIV suggests increased
infection and cytopathicity [Noe et al., 1998]. More
comprehensive studies are required to clarify the
negative and positive effects of cannabinoid receptors
in viral replication.
The immunosuppressant effects of cannabinoids
could be detrimental for certain viral infections, but
in those where host inflammatory and immune
responses are associated with virus immunopatho-
genesis activation of CB receptors, could control viral
pathogenesis [Reiss, 2010]. Viral pathogenesis de-
creased during activation of CB receptors in BDV
[Solbrig and Hermanowicz, 2008], TMEV [Molina-
Holgado et al., 1998], SIV [Molina et al., 2011a,b],
and influenza [Karmaus et al., 2013]. A good example
of a viral infection with a major immune patho-
genesis component is RSV. It has been shown that
opioids and their receptors control RSV replication in
the lung and virus pathogenesis. Opioid receptor
signaling could be beneficial for control of respiratory
viral diseases [Salimi et al., 2013].
Changes in epigenetic mechanisms, including DNA
methylation, histone modification, nucleosome posi-
tioning and non-coding RNA are affected by cannabi-
noid signaling [D’Addario et al., 2013]. The effect of
epigenetic regulation of viral infections by cannabi-
noids has received considerable attention [Molina
et al., 2011b]. For example, CB receptors signal
increased DNA methyltransferase activity by activa-
tion of the p38 and p42/44 MAPK pathways [Paradisi
et al., 2008]. Following the remarkable increase in
DNA methylation, expression of many genes can be
inhibited, especially genes related to cell-virus
J. Med. Virol. DOI 10.1002/jmv
8 Tahamtan et al.
interaction on different levels that effect viral entry,
replication, integration, production, and inflammation
[Molina et al., 2011b].
Cannabinoids could modulate the expression of
miRNAs, a novel class of endogenous non-coding
RNAs that inhibit gene expression by degradation
or translational suppression of the target mRNAs
[Chandra et al., 2014; Zhang, 2008]. For example,
chronic administration of D9-THC induces an intesti-
nal anti-inflammatory microRNA (miR-10a, miR-24,
miR-99b, miR-145, miR-149 and miR-187) expression
during acute SIV infection of rhesus macaques
[Chandra et al., 2014]. The regulation of epigenetic
mechanisms by cannabinoids suggests a novel
hypothesis for controlling viral infection by
In conclusion, cannabinoids can contribute to viral
pathogenesis in certain infections; in others, they can
diminish pathogenesis mediated by multisystemic
effects on host immunity, cell signaling and effector
mechanisms involved in the viral cell cycle. Although
cannabinoids have the therapeutic potential to de-
velop safe and effective treatments, the drawbacks
include insolubility and lack of effectiveness in some
products. These are barriers and require further
study to design and produce products that act with
high solubility and high effectiveness. Caution is
required before the use of pharmaceutical cannabi-
noids to treat patients with viral infections.
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12 Tahamtan et al.
... The anti-inflammatory and immunomodulatory properties of CB2R have been investigated in vitro and in vivo, where CB2R interacts with signaling pathways, enzymes, and factors involved in the modulation of the immune system [122]. Research has mainly focused on the CB2R since these receptors are expressed in immune and immunederived cells, and their activation is known to influence responses to viral infection by altering host immune response, particularly inflammation, along different signaling pathways [123][124][125][126]. Cannabinoids acting on CB2R expressed by immune cells can cause apoptosis, suppression of cell proliferation, inhibition of pro-inflammatory cytokine/ chemokine production, and induction of anti-inflammatory cytokines and regulatory T cells [127,128] Apoptosis is known to be a critical component of host responses to viral infections [129]. ...
... For example, Buchweitz et al., 2008 and Karmaus et al., 2011, mentioned that the role of the endocannabinoid system CB1/CB2 blockade significantly enhanced the inflammatory response to an influenza infection [140,141]. In this sense, Tahamtan et al., 2016 found that infection of RSV can affect the CB1R expression in the lungs (which prominently contain epithelial cells) and importantly displays immunomodulation; the CB1 blockade is associated with the enhanced bronchoalveolar cellular influx, increased IFN-c production, and decreased IL-10 production, together with exaggerated RSV-induced lung histopathology. On the other hand, they suggested that the CB2R is not the only cannabinoid-based mediator of the immune response [122]. ...
... In this sense, Tahamtan et al., 2016 found that infection of RSV can affect the CB1R expression in the lungs (which prominently contain epithelial cells) and importantly displays immunomodulation; the CB1 blockade is associated with the enhanced bronchoalveolar cellular influx, increased IFN-c production, and decreased IL-10 production, together with exaggerated RSV-induced lung histopathology. On the other hand, they suggested that the CB2R is not the only cannabinoid-based mediator of the immune response [122]. Cannabinoid signaling can play a significant role in maintaining immune homeostasis and controlling the magnitude of immune response in various infections. ...
The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established, however, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, and indirect mechanisms of inflammatory / autoimmune origin. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potential promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review we address the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a decrease in viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.
... Endocannabinoids act as agonists of not only G protein-coupled receptors, including cannabinoid receptors (CB1/2), but also TRPV1 and GPR receptors (Lu and Mackie, 2016;Lucaciu et al., 2021). Both cannabinoid receptors are involved in the regulation of redox balance and inflammation, including CB1 by increasing the production of ROS and TNF-a, which is observed, among others, in viral diseases; whereas the CB2 receptor, expressed mainly in cells of the immune system and tissues (Yao and Mackie, 2009), by decreasing the production of ROS and TNF-a, not only reduces both oxidative stress and inflammation (Han et al., 2009;Cinar et al., 2022) but also regulates mitogen-activated protein kinases (MAPKs), and some MAPKs also stimulate phospholipases C and A2 (Correa et al., 2009;Han et al., 2015;Tahamtan et al., 2015). ...
... Moreover, an increase in endocannabinoid levels may lead to an increase in anti-inflammatory cytokines such as IL-10 (Lucaciu et al., 2021). Thus, activation of cannabinoid receptors is important for the pathogenesis of viruses affecting the CNS, such as HHV, HIV, VSV, BDV, measles, mumps, rabies, enteroviruses, La Crosse encephalitis virus, and lymphocytic meningitis virus (Tahamtan et al., 2015). On the other hand, because the CB2 receptor is present in large amounts in immune cells, activation of CB2 receptors exerts a protective effect by suppressing inflammation, oxidative stress, and beneficial regulation of the immune system to viral and bacterial infections (Rom and Persidsky, 2013;He et al., 2019). ...
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One of the growing global health problems are vector-borne diseases, including tick-borne diseases. The most common tick-borne diseases include Lyme disease, tick-borne encephalitis, human granulocytic anaplasmosis, and babesiosis. Taking into account the metabolic effects in the patient’s body, tick-borne diseases are a significant problem from an epidemiological and clinical point of view. Inflammation and oxidative stress are key elements in the pathogenesis of infectious diseases, including tick-borne diseases. In consequence, this leads to oxidative modifications of the structure and function of phospholipids and proteins and results in qualitative and quantitative changes at the level of lipid mediators arising in both reactive oxygen species (ROS) and ROS enzyme–dependent reactions. These types of metabolic modifications affect the functioning of the cells and the host organism. Therefore, links between the severity of the disease state and redox imbalance and the level of phospholipid metabolites are being searched, hoping to find unambiguous diagnostic biomarkers. Assessment of molecular effects of oxidative stress may also enable the monitoring of the disease process and treatment efficacy.
... CNR1 (cannabinoid receptor 1 [CB1]) is the hub of the green- Table 3 for explanation of column titles and Table 1 for listing of cases used for each OB neuronal marker. yellow module and mediates the biological activity of both endogenous and exogenous cannabinoids centered on psychoactive functions (184). There are multiple lines of evidence regarding the effects of cannabinoid receptors on viral infection. ...
... Activation of CB1 inhibits the production of proinflammatory mediators, such as NO or TNFa, and inhibits Ca2þ channels. On one hand, the activation of CB1 increases the progression of viral diseases through an immunosuppressive effect, but on the other hand it might inhibit the immune effects derived from the viral infection by eliciting an immunoprotective profile (184). In our study we see a dysregulation of the network regulated by CB1, and we hypothesize this might be a feedback effect aimed at reducing the neuroinflammatory state induced by the viral infection. ...
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Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.
... In mice suffering from acute lung injury caused by lipopolysaccharide (LPS)-induced infection, a one-off CBD dose (20 mg/kg) administered prior to infection decreased the production of pro-inflammatory TNF, IL-6, MCP-1, and MIP-2 [146]. In human T-cells, ∆9-tetrahydrocannabinol (THC), another cannabinoid, reduced the production of IFN-α and increased the levels of Th2 cytokines (IL-4 and IL-10) in a concentration dependent manner after dendritic cell presentation of foreign antigens to T-cells [147]. THC is thought to interact with cannabinoid receptors on T-cells to suppress their activation, thereby dampening the inflammatory phenotype. ...
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Emerging and re-emerging viral diseases have increased in number and geographical extent during the last decades. Examples include the current COVID-19 pandemic and the recent epidemics of the Chikungunya, Ebola, and Zika viruses. Immune responses to viruses have been well-characterised within the innate and adaptive immunity pathways with the outcome following viral infection predominantly attributed to properties of the virus and circumstances of the infection. Perhaps the belief that the immune system is often considered as a reactive component of host defence, springing into action when a threat is detected, has contributed to a poorer understanding of the inherent differences in an individual’s immune system in the absence of any pathology. In this review, we focus on how these host factors (age, ethnicity, underlying pathologies) may skew the T helper cell response, thereby influencing the outcome following viral infection but also whether we can use these inherent biases to predict patients at risk of a deviant response and apply strategies to avoid or overcome them.
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Practical guide about endocannabinoid medicine and its clinical applications. Guia prático sobre medicina endocanabinoide e suas aplicações clínicas. #medicalcannabis #endocannabinology
Computational tools in drug discovery involve the use of algorithms in predicting properties of potential drugs as ligands as well as biological targets in structural forms. This dates back to more than 30 years ago and have been perfected with time and advancement of technology. They are reliable to varying extents depending on the nature of the study, complexity among other factors. Computational tools help medicinal chemists, computational chemists, and structural biologists to design and optimize potential drugs as early as possible and reduce or completely avoid attrition in the drug discovery pipeline. The search for drugs to cure or manage COVID-19 is made relatively easier and more efficient by the use of computational tools to help understand the ADMET properties of possible drugs under development. This chapter demonstrates how computational tools in cheminformatics and machine learning can be used in the fight against COVID-19 from a medicinal chemistry perspective using selected parameters.
The coronavirus disease 2019 (COVID-19) was identified as the cause of an outbreak of respiratory illness in Wuhan in 2019. Some of the antivirals presently being tried are known anti-HIV (combination of lopinavir and ritonavir) and the rejected anti-ebola virus (remdesivir) drugs. Others are chloroquine, hydroxychloroquine and azithromycin. Till date, there is no specific antiviral treatment that has proven effective in the management of the pandemic. The infected victims primarily rely on symptomatic treatments and supportive care. This COVID-19 outbreak has triggered researchers worldwide to embark on more high-quality researches, in addition to the preventive measures, to manage the public health emergency in both the short- and long-term. Membrane lipids like cholesterol, glycerophospholipids and sphingolipids play key role in modification of intracellular membrane structures for virus replication. This chapter discussed the roles of membrane lipids in coronavirus replication, and inhibition of lipids biosynthesis for possible management of coronavirus disease.
Drug repurposing involves the process of investigating already existing drugs with an aim to use them for different therapeutic purposes than the intended one. This approach is relatively faster, less costly, and reliable in terms of safety as the drug under study is already derisked and known for its other chemistry and pharmacokinetic properties. With these benefits in mind, it is a very reliable way to undertake drug development for emerging diseases such as COVID-19 which demand immediate interventions to slow or completely stop its havoc on mankind. One of the biggest challenges that drug repurposing has is the possibility of the occurrence of new mechanisms of action between the drug ligand and some proteins in the human physiology. Drug repurposing appears to have settled in the meantime in drug development, though more studies in the future will be warranted particularly in regards to resistance.
Coronavirus Drug Discovery SARS-CoV-2 (COVID-19) Prevention, Diagnosis, and Treatment
Various individuals, community organizations and institutions must be involved in planning and developing a cure for the COVID-19 flu pandemic. In addition to governmental organizations, those who need to be involved in the process are responsible for implementing pandemic plans. There should be a balance between centralized national control and regional and local communities through the effective implementation of the guidelines. There is a need to introduce social distancing and to study and isolate cases to contain disease spread. Due to the amendment and tightening of the law "SARS-CoV-2" in many countries, special attention should be paid to respect for citizens, especially national minorities. That is why it is necessary to protect freedom statements and providing access to critical information; make sure that quarantines, locks and travel bans comply with legal standards; persons.
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Unlabelled: Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of Δ9-tetrahydrocannabinol (Δ9-THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including Δ9-THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of Δ9-THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving Δ9-THC (n=3) and SIV-infected macaques administered either vehicle (VEH/SIV; n=4) or THC (THC/SIV; n=4). Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ∼28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation. Importance: Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection. Previously, we showed that chronic treatment of SIV-infected macaques with Δ9-tetrahydrocannabinol (Δ9-THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation. Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine at 60 days p.i. These included several miRNAs bioinformatically predicted to directly target CXCL12, a chemokine known to regulate lymphocyte and macrophage trafficking into the intestine. Specifically, miR-99b was significantly upregulated in THC-treated SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4), a reactive oxygen species generator known to damage intestinal epithelial cells. Elevated miR-99b expression was associated with a significantly decreased number of NOX4+ epithelial cells in the intestines of THC-treated SIV-infected macaques. Overall, our results show that selective upregulation of anti-inflammatory miRNA expression contributes to THC-mediated suppression of gastrointestinal inflammation and maintenance of intestinal homeostasis.
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Background and Aim To evaluate in anti-HCV-positive patients the clinical impact of the rs35761398 variant of the CNR2 gene leading to the substitution of Gln (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with Arg (R). Patients and Methods 253 consecutive anti-HCV-/HCV-RNA-positive patients were enrolled, of whom 53 were HCV carriers with persistently normal ALT (PNALT group) and 200 had a history of steadily abnormal serum ALT values (abnormal ALT group). All patients were naive for antiviral therapy and were screened for the CNR2 rs35761398 polymorphism by a TaqMan assay. Results Subjects in the PNALT group, compared with those in the abnormal ALT group were older (58.5±12 vs. 50.7±12.4 years, p = 0.001), more frequently female (66% vs. 42%, p = 0.003), with lower body massindex (BMI) (24.5±3.1 vs. 26.6±4.6, p = 0.003), and more frequently with HCV genotype 2 (43.1% vs 17.7%, p = 0.0002) and CB2-63 QQ variant (34% vs. 11%, p = 0.0001). Considering all 253 patients, no difference in the demographic, biochemical, or virological data was observed between patients in the different CB2-63 variants. The logistic regression analysis identified CB2-63 QQ, HCV genotype 2, older age and lower BMI as independent predictors of PNALT (p<0.00001). Discussion The CB2-63 QQ variant in HCV patients was independently associated with the PNALT status.
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Background Insulin resistance is highly prevalent in patients with chronic hepatitis C (CHC) and to some extent accounts for fibrosis and reducing viral eradication. Activated cannabinoid 1 receptor (CB1R) signaling has been implicated in the development of phenotypes associated with insulin resistance and steatosis. We investigated the role of the endocannabinoid system in glucose metabolism disorders induced by hepatitis C virus (HCV) replication. Methods Human hepatic stellate cells (HSC; LX-2 cells) were co-cultured with Huh-7.5 cells or Huh-7.5 cells harboring HCV replicon (replicon cells). Endocannabinoid levels were then measured by liquid chromatography/mass spectrometry. The expression of CB1R and its downstream glucose metabolism genes in hepatocytes were determined by real-time PCR and Western blot. Glucose uptake by hepatocytes and glucose production were measured. Glucose metabolism tests and measurements of HCV RNA levels and nonstructural protein 5A (NS5A) levels were taken after treatment with CB1R agonist arachidonyl-2-chloroethanolamide (ACEA) or antagonist AM251. Results Compared to the co-culture with Huh-7.5 cells, the level of 2-arachidonoylglycerol (2-AG) and the CB1R mRNA and protein levels increased in the co-culture of LX-2 cells with replicon cells. The activation of CB1R decreased AMP-activated protein kinase (AMPK) phosphorylation, inhibited cell surface expression of glucose transporter 2 (GLUT2), and suppressed cellular glucose uptake; furthermore, it increased cyclic AMP response element-binding protein H (CREBH), then up-regulated phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes and down-regulated the glucokinase (GK) gene, thus promoting glucose production. Interferon treatment restored the aforementioned changes. CB1R antagonist improved glucose metabolism disorders by an increase in glucose uptake and a decrease in glucose production, and inhibited HCV replication. Conclusions HCV replication may not only increase the 2-AG content, but may also up-regulate the expression of CB1R of hepatocytes, then change the expression profile of glucose metabolism-related genes, thereby causing glucose metabolism disorders of hepatocytes and promoting HCV replication. Treatment with CB1R antagonist improved glucose metabolism disorders and inhibited viral genome replication.
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While cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC), have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, since they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In the present study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18 and GPR55, as well as the ion channel TRPV1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, TRPV1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.
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Our studies have demonstrated that chronic Δ9-tetrahydrocannabinol (THC) administration results in a generalized attenuation of viral load and tissue inflammation in simian immunodeficiency virus (SIV)-infected male rhesus macaques. Gut-associated lymphoid tissue is an important site for HIV replication and inflammation that can impact disease progression. We used a systems approach to examine the duodenal immune environment in 4-6 yr-old male rhesus monkeys inoculated intravenously with SIVMAC251 after 17 mo of chronic THC administration (0.18-0.32 mg/kg, intramuscularly, twice daily). Duodenal tissue samples excised from chronic THC- (N=4) and vehicle (VEH)-treated (N=4) subjects at ~5 mo post-inoculation showed lower viral load, increased duodenal integrin beta 7+ (β7) CD4+ and CD8+ central memory T cells, and a significant preferential increase in Th2 cytokine expression. Gene array analysis identified 6 genes to be differentially expressed in intestinal samples of the THC/SIV animals when compared to those differentially expressed between VEH/SIV and uninfected controls. These genes were identified to have significant participation in 1) apoptosis; 2) cell survival, proliferation, and morphogenesis; and 3) energy and substrate metabolic processes. Additional analysis comparing the duodenal gene expression in THC/SIV vs. VEH/SIV animals identified 93 differentially expressed genes that participate in processes involved in muscle contraction, protein folding, cytoskeleton remodeling, cell adhesion and cell signaling. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC/SIV subjects. Our results indicate that chronic THC treatment modulated duodenal T cell populations, favored a pro-Th2 cytokine balance, and decreased intestinal apoptosis. These findings reveal novel mechanisms that may potentially contribute to cannabinoid-mediated disease modulation.
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The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation. The specific roles of currently identified endocannabinoids that act as ligands at endogenous cannabinoid receptors within the central nervous system (primarily but not exclusively CB 1 receptors) and in the periphery (primarily but not exclusively CB 2 receptors) are only partially elucidated, but they do exert an influence on nociception. Exogenous plant-based cannabinoids (phytocannabinoids) and chemically related compounds, like the terpenes, commonly found in many foods, have been found to exert significant analgesic effects in various chronic pain conditions. Currently, the use of Δ9-tetrahydrocannabinol is limited by its psychoactive effects and predominant delivery route (smoking), as well as regulatory or legal constraints. However, other phytocannabinoids in combination, especially cannabidiol and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles. This review will provide the reader with the foundational basic and clinical science linking the endocannabinoid system and the phytocannabinoids with their potentially therapeutic role in the management of chronic pain.
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Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake), morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia.
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Cannabinoids are promising therapies to support neurogenesis and decelerate disease progression in neuroinflammatory and degenerative disorders. Whether neuroprotective effects of cannabinoids are sustainable during persistent viral infection of the CNS is not known. Using a rodent model of chronic viral encephalitis based on Borna Disease (BD) virus, in which 1 week treatment with the general cannabinoid WIN 55,212-2 has been shown to be neuroprotective (Solbrig et al., 2010), we examine longer term (2 week treatment) effects of a general (CB1 and CB2) cannabinoid receptor agonist WIN55,212-2 (1mg/kg ip twice per day) or a specific (CB2) cannabinoid receptor agonist HU-308 (5mg/kg ip once daily) on histopathology, measures of frontostriatal neurogenesis and gliogenesis, and viral load. We find WIN and HU-308 differ in their ability to protect new BrdU(+) cells. The selective CB2 agonist HU increases BrdU(+) cells in prefrontal cortex (PFC), significantly increases BrdU(+) cells in striatum, differentially regulates polydendrocytes vs microglia/macrophages, and reduces immune activation at a time WIN-treated rats appear tolerant to the anti-inflammatory effect of their cannabinoid treatment. WIN and HU had little direct viral effect in PFC and striatum, yet reduced viral signal in hippocampus. Thus, HU-308 action on CB2 receptors, receptors known to be renewed during microglia proliferation and action, is a nontolerizing mechanism of controlling CNS inflammation during viral encephalitis by reducing microglia activation, as well as partially limiting viral infection, and uses a nonpsychotropic cannabinoid agonist.
The aim of this study was to assess the effect of select cannabinoids on human immunodeficiency virus type 1 (HIV-1) transactivating (Tat) protein-enhanced monocyte-like cell adhesion to proteins of the extracellular matrix (ECM). Collagen IV, laminin, or an ECM gel were used to construct extracellular matrix layers. Human U937 monocyte-like cells were exposed to Tat in the presence of ∆(9)-tetrahydrocannabinol (THC), CP55,940, and other select cannabinoids. Cell attachment to ECM proteins was assessed using an adhesion assay. THC and CP55,940 inhibited Tat-enhanced attachment of U937 cells to ECM proteins in a mode that was linked to the cannabinoid receptor type 2 (CB2R). The cannabinoid treatment of Tat-activated U937 cells was associated with altered β1-integrin expression and distribution of polymerized actin, suggesting a modality by which these cannabinoids inhibited adhesion to the ECM. The blood-brain barrier (BBB) is a complex structure that is composed of cellular elements and an extracellular matrix (ECM). HIV-1 Tat promotes transmigration of monocytes across this barrier, a process that includes interaction with ECM proteins. The results indicate that cannabinoids that activate the CB2R inhibit the ECM adhesion process. Thus, this receptor has potential to serve as a therapeutic agent for ablating neuroinflammation associated with HIV-elicited influx of monocytes across the BBB.
Cannabinoid receptor 2 (CB2) is highly expressed in immune cells and stimulation decreases inflammatory responses. We tested the idea that selective CB2 activation in human monocytes suppresses their ability to engage the brain endothelium and migrate across the blood-brain barrier (BBB), preventing consequent injury. Intravital videomicroscopy was used to quantify adhesion of leukocytes to cortical vessels in lipopolysaccharide-induced neuroinflammation, after injection of ex vivo CB2-activated leukocytes into mice; CB2 agonists markedly decreased adhesion of ex vivo labeled cells in vivo. In an in vitro BBB model, CB2 activation in monocytes largely attenuated adhesion to and migration across monolayers of primary human brain microvascular endothelial cells and diminished BBB damage. CB2 stimulation in monocytes down-regulated active forms of integrins, lymphocyte function-associated antigen 1 (LFA-1), and very late antigen 4 (VLA-4). Cells treated with CB2 agonists exhibited increased levels of inhibitory sites of the actin-binding proteins cofilin and VASP, which are upstream regulators of conformational integrin changes. Up-regulated by relevant stimuli, Rac1 and RhoA were suppressed by CB2 agonists in monocytes. CB2 stimulation decreased formation of lamellipodia, which play a key role in monocyte migration. These results indicate that selective CB2 activation in leukocytes decreases key steps in monocyte-BBB engagement, thus suppressing inflammatory leukocyte responses and preventing neuroinflammation.