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Journal of Medical Virology
Effects of Cannabinoids and their Receptors on
Viral Infections
Alireza Tahamtan,
1
Masoumeh Tavakoli-Yaraki,
2
Tomasz P. Rygiel,
3
Talat Mokhtari-Azad,
1
and Vahid Salimi
1
*
1
Departmentof Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
2
Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
3
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
INTRODUCTION
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-
22926.
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.
E-mail: vsalimi@sina.tums.ac.ir
Accepted 1 June 2015
DOI 10.1002/jmv.24292
Published online in Wiley Online Library
(wileyonlinelibrary.com).
C2015 WILEY PERIODICALS, INC.
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.,
2010].
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,
2013].
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
2þ
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
þ
(GIRK) channels Play a major role in determining
neuronal excitability
Mackie et al. [1995]
Inhibits Na
þ
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
differentiation
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.
[2006]
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
2þ
concentrations. This would impair Ca
2þ
dependent
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.
[1986]
Induces phosphorylation of p44/42 MAPK and PKB/Akt
via PI3K pathway
Neuroprotective effect Offertaler et al.
[2003]
Reduces Erk1/2 and JNK1/2 activation Anti-inflammatory effect Gertsch et al.
[2008]
Activation of phospholipases C Leading to release Ca
2þ
Shoemaker et al.
[2005]
Regulates small G proteins such as Rho, Rac, Cdc42 Suppress neutrophil migration Kurihara et al.
[2006]
Activates JNK via the PI3K/Akt pathway Neuroprotective effect Viscomi et al.
[2009]
Decreases CXCR4-activation mediated G-protein activity and
alters cytoskeletal reorganization
Inhibit actin reorganization
and impair productive infection
Costantino et al.
[2012]
Triggers apoptosis in immune cells Immunosuppressive effect Rom and Persidsky
[2013]
Inhibits the release of neurotoxic factors and suppress
microglia activation
Anti-inflammatory effect Klegeris et al.
[2003]
Preventes neuronal injury during neuroinflammation via
upregulation of MAPK phosphatase-1(MKP-1)
Protects neurons from
inflammatory damage
Eljaschewitsch
et al. [2006]
Reduces iNOS production via inhibition of ERK-1/2
phosphorylation in microglia during inflammation
Anti-inflammatory effect Merighi et al.
[2011]
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.
[2010]
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.
[2008]
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
Influenza
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
2þ
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
Influenza
virus
D9-THC suppress DC, Mac/MФand inflammatory myeloid cell responses, in a
mechanism involving CB1 and/or CB2 receptors activation
Karmaus et al.
[2013]
Deletion of CB1 and CB2 receptors exacerbates APC function to increase
inflammation and cellular immunity during influenza infection
Karmaus et al.
[2011]
D9-THC modulate immunological and pulmonary airway responses to influenza virus
through CB receptors dependent and independent mechanisms
Buchweitz et al.
[2008]
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.
[2007]
HCV The CB2 polymorphism (CB2-63 QQ variant) associate with more severe
inflammation and hepatocellular necrosis in patients with HCV infection
Coppola et al.
[2014a]
The CB2 polymorphism (CB2-63 QQ variant) independently associate with
persistently normal aminotransferase serum levels in chronic HCV
Coppola et al.
[2014b]
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.
[2008]
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
H
́
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.
[2013]
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
CD4
þ
T cells
Costantino et al.
[2012]
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.
[2011]
Cannabinoids using prevent the impairment of network function produced by HIV-1
gp120
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
[2010]
Elevated levels of SDF-1a/CXCL12 in the brain diminish the thermoregulatory
response of cannabinoids
Benamar et al.
[2009]
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
þ
T and microglial cells
Petersona et al.
[2004]
Cannabinoids alter HIV RNA levels by immune modulation or cannabinoid-protease
inhibitor interactions
Abrams et al.
[2003]
The CB activation reduce theTat induced cytotoxicity, by the modulation of the
L-arginine/NO pathway
Esposito et al.
[2002]
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.
[2004]
D9-THC elicits dysfunction in CTL by altering effector cell-target cell postconjugation
events
Fischer-Stenger
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]
continued
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.
HIV
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.,
2010].
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
þ
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
[1985]
Other
viruses
D9-THC enhance severity and duration of symptoms in vaccinia virus infected mice Huemer et al.
[2011]
Cannabinoids abusing interfere with antibody response after a generalised
orthopoxvirus infection
Huemer et al.
[2007]
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
macaques
LeCapitaine et al.
[2011]
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.
[2003]
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
þ
and CD8
þ
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.,
1986].
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
Sword
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
þ
lymphocytes
[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
cannabinoids.
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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