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Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation of NOS-1, inhibition of Ca(2+) activity by cannabinoids, increased viral replication and disease. This review examines the effect(s) of cannabinoids and their antagonists in viral infections.
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Pharmaceuticals 2010, 3, 1873-1886; doi:10.3390/ph3061873
pharmaceuticals
ISSN 1424-8247
www.mdpi.com/journal/pharmaceuticals
Review
Cannabinoids and Viral Infections
Carol Shoshkes Reiss
Department of Biology, Center for Neural Science, NYU Cancer Institute and Department of
Microbiology, New York University, 100 Washington Square East, New York, NY, 10003, USA;
E-Mail: carol.reiss@nyu.edu; Tel.: +1-212-998-8269; Fax: +1-212-995-4015
Received: 21 May 2010; in revised form: 28 May 2010 / Accepted: 9 June 2010 /
Published: 9 June 2010
Abstract: Exogenous cannabinoids or receptor antagonists may influence many cellular
and systemic host responses. The anti-inflammatory activity of cannabinoids may
compromise host inflammatory responses to acute viral infections, but may be beneficial in
persistent infections. In neurons, where innate antiviral/pro-resolution responses include
the activation of NOS-1, inhibition of Ca
2+
activity by cannabinoids, increased viral
replication and disease. This review examines the effect(s) of cannabinoids and their
antagonists in viral infections.
Keywords: pathogens; virus infection; immunomodulation; inflammation
1. Introduction
Both endogenous and exogenous cannabinoids can influence the course of infections in vitro and in
vivo. This review will focus on viral infections of mammals, but will also describe what is known
about other infections. Readers are directed to the excellent accompanying reviews in this issue which
expertly discuss the clinical trials, cell biology, mechanisms of action, impact on inflammation, clinical
applications, and so forth.
Cannabinoids may act either through the CB
1
or the CB
2
receptor, which are found on distinct cell
types. The CB
1
receptor is found on neurons as well as some astrocytes and skeletal muscle cells;
neurons are frequently the target of viral infection. Engagement of the CB
1
receptor by its endogenous
or exogenous agonists may inhibit the release of Ca
2+
from intracellular or extracellular stores. Since
many important intracellular proteins are Ca
2+
-dependent for activation, signal transduction through
the CB
1
receptor may impair these secondary pathways and have a profound influence on the ability of
viruses to replicate in neurons.
OPEN ACCESS
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In contrast, the response of cells expressing the CB
2
receptor may influence not only the responses
in that cell, but may alter the course of the host innate and adaptive immune response to the pathogen,
suppressing inflammation and the development of virus-specific cellular and humoral responses. The
outcome on the viral infection will depend on whether inflammation is beneficial or pathogenic in the
specific case.
2. Discussion
When a host is infected with a virus, there is a dynamic competition between the ability of the host
to first marshal innate (hours to days) and then adaptive immunity (>7 days post infection) vs. the
replication and spread of the virus first within the host and then to additional susceptible individuals.
When a virus is able to out-pace the containment efforts, the host may succumb. Pathology may result
from damage to tissues by viral-induced cellular apoptosis or necrosis, or alternatively, host immune
responses may result in immunopathology or the perceived symptoms of the infection. If, however,
innate and adaptive immunity successfully suppress viral replication, specific life-long immunity
may result.
In order to understand the influences on the host response which may be the result of cannabinoids,
it is important to examine some of the cellular pathways which are dependent on Ca
2+
-dependent
enzymes. Table 1 indicates some of the well characterized pathways involved and their potential
impact on viral infections.
The common recurring impact of Ca
2+
-dependent enzymes is a role in inflammation. This ranges
from regulation of many signal transduction pathways, production of pro-inflammatory and
pro-resolving lipid mediators downstream of arachidonic acid, to activation of Nitric Oxide Synthase
and the production of reactive nitrogen intermediates, to proteolytic enzymes which remodel the
cytoskeleton or extracellular matrix, and apoptosis.
Inflammation is essential for recruitment of both innate and adaptive immune cells to the site of
infection to control virus production and limit spread, and then to promote recovery. Inflammation is
comprised not only of non-specific cells (sequentially these are polymorphonuclear leukocytes, natural
killer cells, macrophages) and then pathogen-specific T lymphocytes recruited from circulation, and
activation of antibody-secreting B lymphocytes, but also induction of production and secretion of
cytokines, chemokines, interferons, complement components, acute phase reactants, reactive oxygen
and nitrogen intermediates, and other mediators [24–26]. Readers are referred to the accompanying
review by Bani, Mannaioni, Passani, and Masini [27]. Thus, many of these critical pathways may be
impaired or compromised when endogenous or exogenous cannabinoids are present during an
infection [28].
Cannabinoids have been used both recreationally by groups of people who have viral infections, and
experimentally by scientists investigating their impact in vitro or in animal models. Table 2 presents
what has been published about these populations in peer reviewed journals. In most of the infections
studied (Table 2), it is apparent that cannabinoid treatment, whether in vitro or in vivo, had profound
impact on the virus-host (cell) interactions. For HSV-2, HIV-1, KSHV, influenza and VSV viral
replication, or surrogate measures of infection, were found to be substantially increased upon
cannabinoid treatment [30,34,39,50,52,63]. In HIV-1 infection, syncytia formation was enhanced, and
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monocytes were stickier on endothelial cells [57,58]. In one study, KHSV was more likely to exit
latency and enter lytic infection when transformed cells were treated with THC [39], however, another
study found the opposite result in several herpesvirus infections [38].
Table 1. Some Ca
2+
-dependent enzymes which may be inhibited by Cannabinoids and
speculated role in host responses relevant for viral infections.
Enzyme
primary/secondary
Pathways
Ref.
Role(s) in viral
infection-host
responses
cPhospholipase A
2
Arachidonic acid metabolites (prostaglandins,
leukotrienes, lipoxins, resolvins) and
inflammation
[1,2] Inflammation and its
resolution
Phospholipase C
- Receptor-mediated tyrosine
kinase
Production of Inositol 1,4,5-triphosphate from
phosophotidylinositol
[3] Signal transduction
Phospholipase D
1
Exocytosis in neuroendocrine cells [4] Neurotransmission
Calcineurin Activation of NFAT—gene expression [5,6] Signal transduction
Ca
2+
-Calmodulin
- Nitric oxide synthase-1
- Nitric oxide synthase-3
Conversion of argenine to NO in neurons and
endothelial cells; production of ONOO-, -SNO,
-R-NO
2
Inhibition of viral infection
[7–12]
Anti-viral; NO
2
-
decoration of viral
proteins; capillary
dilation; inflammation
Ca
2+
-Calmodulin dependent
protein kinases
- CREB
- CaMKK activation of
AMPK
Wnt-2-dependent dendrite growth &
cardiomyogenesis
Energy, epithelial cell polarity
T cell activation
[13–17] Adaptive immune
responses;
inflammation
Calpains [Ca
2+
-dependent
proteases]
Neutral proteases [many tissues]
Cell membrane fusion, synaptic remodeling,
activating PKC, remodeling cytoskeleton,
transcription factors
[18–20] Cytoskeletal plasticity,
cell migration,
inflammation
Matrix metalloproteinases Extracellular matrix remodeling, inflammation [21] Inflammation
Calpastatin Cell fusion in fertilization [22] Formation of
heterokaryons
/giant cells
Transglutaminases Cross-linking/deamination of proteins –wound
healing, tissue repair, apoptosis, cell cycle
control, inflammation and fibrosis
[23] Inflammation, fibrosis,
cell cycle and
programmed cell death
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Table 2. Cannabinoids and Viral Infections.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
HSV-2,
L. monocyto-
genes
In vivo Δ9-THC decreased
resistance to
LD
50
systemic infection [29]
HSV-2 In vivo Δ9-THC increased
shedding
increased
severity of
lesions &
mortality
delayed onset of
DTH response
vaginal model
B6C3H F
1
mouse
[30]
HSV-2 In vivo Δ9-THC decreased Type I
IFN response
i.v. infection [31]
HSV-2 In vivo Δ9-THC decreased
resistance to
infection;
increased
severity of
lesions
vaginal guinea pig
model
[32]
HSV-1,-2 In
vitro
Δ9-THC failed to
replicate
antiviral effect in
human & monkey
cells
[33]
HSV-2 In
vitro
Δ9-THC 100-fold
increase in
released
virus
Vero cells,
increased CPE
[34]
HSV-2 both Δ9-THC decreased T cell
proliferation
B6C3H F
1
mice
immunized then T
cells cultured
[35]
HSV In
vitro
Δ9-THC decreased
infectivity
in TC
virus incubated
with THC
[36]
HSV-1 both Δ9-THC decreased CD8
CTL activity
C3H mice
immunized, L929
targets
[37]
EBV,
KSHV,
HVS,
HSV-1,
MHV-68
In vivo Δ9-THC Immediate
early ORF
promoter
activity
inhibited
reactivation
from latency
inhibited
latently infected B
cells in tissue
culture
[38]
KSHV In vivo Δ9-THC increased
viral load
increased
efficiency of
infection,
activation of
lytic switch
increased
transformation of
endothelial cells
primary human
dermal
microvascular cells
[39]
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Table 2. Cont.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
Cowpox In vivo Marijuana
cigarettes
generalized
infection
weak Ab
production, no
neutralizing Abs
Case report [40]
TMEV In
vitro
Anandamide decreased release
of NO2- and
TNF-α
NO is antiviral for
TMEV
[41;42]
TMEV In
vitro
Anandamide increased IL-6
production
astrocyte culture
B6 and SJL mice
[43]
TMEV In vivo WIN-55,212 ameliorates
progression of
autoimmune
disease TMEV-
IDD
decreased DTH,
decreased IL-1,
IL-6, IFN-
γ , TNF-α,
TMEV-IDD a
mouse model of
MS
[44]
TMEV In vivo OMDM1,
OMDM2
ameliorated
motor
symptoms
decreased MHC
II, inhibited
NOS-2, reduced
proinflammatory
cytokines
TMEV-IDD
proposed MS
therapy with
cannabinoids
[45]
TMEV In
vitro
JWH-133
SR144558
role of CB
2
receptors in
anti-
inflammatory
actions
reduced IL-
12p40, reduced
ERK1/2
signaling
[46]
TMEV In
vitro
WIN-55,212 CB
2
-dependent
COX-2
induction
increased vs.
TMEV-alone
role of PI3 kinase
pathway in CB
2
but MAPK for
TMEV signaling
proposed role on
blood-flow and
immune activity
[47]
TMEV In vivo Palmitoyl-
ethanol-
amine
reduction in
motor disability
in TMEV-IDD
anti-
inflammatory
effect
TMEV-IDD
[48]
TMEV both WIN-55,212 inhibited ICAM
& VCAM on
endothelium;
role for PPAR-γ
receptors in
mechanism
reduced
inflammation
TMEV-IDD
[49]
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Table 2. Cont.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
Influenza In vivo Δ9-THC HA mRNA
increased
inflammation,
metaplasia of
mucous cell
decreased CD4,
CD8, and
macrophage
recruitment
[50]
Influenza In vivo Δ9-THC HA mRNA
decreased in
CB
1
/CB
2
KO
mice
THC-mediated
airway
pathology +/-
CB
1
/CB
2
KO mice had
increased CD4
and IFN-γ
recruitment
CB
1
/CB
2
KO mice [51]
VSV In vitro WIN-55,212 increased
viral titers
CB
1
-dependent;
decreased NOS-
1 activity
antagonized IFN-
γ-mediated
antiviral pathway
suggested disease
progression likely
in neurons/viral
encephalitis
[52]
BDV In vivo WIN-55,212 protected BrdU-
positive neural
progenitor cells
in striatum
suppressed
microglial
activation
suggested treatment
of encephalitis with
microglial
inflammation and
neuro-degeneration
[53]
HCV In vivo Marijuana
cigarettes
progression of
liver fibrosis
epidemiological
study
[54]
HCV In vivo Oral
cannabinoids
improved
weight
no viral markers
or immune
markers studied
7 week clinical trial
for anorexia and
nausea
[55]
HCV In vivo Marijuana
cigarettes
progression of
liver fibrosis;
increased
disease severity
clinical
pathological survey
of 204 HCV
patients
[56]
HIV-1 In vitro Δ9-THC, CP-
55,940, WIN-
55,212
increased syn-
cytia formation
MT-2 cells
(CB
1
& CB
2
+
)
speculate
cannabinoids
enhance HIV-1
infection
[57]
HIV-1 In vitro anandamide increased
adherence for
monocytes
uncoupled NO
release, inhibited
NO
human saphenous
vein or internal
thoracic artery;
speculate higher
titers in vivo
[58]
HIV-1 Tat In vitro WIN-55,212 reduced tat-
induced
cytotoxicity
inhibited NOS-2
activity
C6 rat glioma cell
line
[59]
HIV-1 In vivo Marijuana
cigarettes
increased
appetite
insufficient
numbers of
individuals
3 week trial [60]
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Table 2. Cont.
Viral
pathogen
In vivo
In vitro
Agonist /
Antagonist
Titer
change
Pathogenesis
Inflammation
Immunoregu-
lation
Comments Ref.
HIV-1 In vivo Marijuana
cigarettes
mRNA
unchanged
CD4+ and CD8+
cells unchanged
3 week trial,
placebo-controlled
[61]
HIV-1 WIN-55,212 inhibited
expression
CD4 and microglial
cultures
[62]
HIV-1 In vivo THC increased
viral
replica-tion
50-fold
decreased CD4
IFN-γ-producing
cells, increased
co-receptor
expression
scid-Hu mouse
model
[63]
HIV-1
Gp120
In
vitro
2-AG,
CP55940
inhibited Ca
+2
-
flux-induced
substance P,
decreased
permeability
model of BBB, co-
culture of Human
brain microvascular
endothelial cells
and astrocytes
[64]
HIV-1 In vivo WIN-55,212 dose-related
hypothermia in
mouse pre-optic
anterior
hypothalamus
infusion
WIN-55,212 is
antagonist for
SDF-1a/
CXCL12/
CXCR4 [HIV-1
coReceptor]
pathway
mouse model for
HIV-thermoreg-
ulation by direct
injection of WIN-
55,212 to brain
POAH center
[65]
HIV-1 Tat In
vitro
CP55940,
Δ9-THC
CB
2
-dependent
inhibition of
U937 migration
to Tat
possible anti-
inflammatory
mechanism
U937 cells in
culture
[66]
Legend: BDV, Borna disease virus; EBV, Epstein-Barr virus; HCV, Hepatitis C virus; HIV, Human
immunodeficiency virus; HSV, Herpes simplex virus; HVS, Herpes virus samirii; KO, knock-out mice;
KSHV, Kaposi's sarcoma herpes virus; L. monocytogenes, Listeria monocytogenes; MHV-68, Murine herpes
virus-68; TMEV, Theiler's murine encephalomyelitis virus; VSV, Vesicular stomatitis virus.
Disease was more severe in HSV-2-infected guinea pigs which were treated with THC [29,30,32].
In HCV infections, clinical studies have shown a profound co-morbidity of recreational cannabinoid
use, for disease progression [54,56]. One case report of Cowpox infection, a very rare human pathogen,
indicated that recreational use of cannabinoids was associated with generalized infection and very poor
immune responses to the virus [40].
In contrast, in those infections where host inflammatory responses are often associated with
pathology, and not with clearance and recovery, cannabinoid treatment of hosts was beneficial. These
included one mouse model of multiple sclerosis, the Theiler's murine encephalomyelocarditis virus
(TMEV)-induced demyelinating disease (IDD), where progression towards the paralysis and disability
were ameliorated [44,45,48] and in Borna disease virus (BDV) where neural progenitors were
protected from proinflammatory cytokine-mediated damage [53] infections. TMEV-IDD is
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characterized by microglial activation in the spinal cord of mice and a T cell-mediated autoimmune
demyelinating disease, triggered by the viral infection [42,67–69]. Persistent BDV infection of the
central nervous system is associated with immunopathology associate with inflammation and
production of pro-inflammatory cytokines, induction of NOS-2 in microglia, and breakdown of the
blood-brain barrier [70–73]. In both BVD and TMEV-IDD, the targets for the anti-inflammatory
effects of the cannabinoid treatment are lymphocytes and mononuclear cells.
Two excellent reviews of the impact of cannabinoids on bacterial, yeast, and protozoan infections
were published in the same issue of Journal of Neuroimmunology [26,74]. These infections included
Treponema pallidum (Syphilis), Legonella pneumophila (Legionnaires' disease), Staphylococci aureus
and S. albus, Listeria monocytogenes, Candida albicans (Thrush), and Naegleria fowleri. Both reviews
concluded that THC significantly reduced host resistance to infection of experimental animals, and
speculated that similar host compromise would be found in man. In the more than 12 years since those
reviews were published, additional findings have extended the serious consequences of cannabinoids
on host responses to pathogens and opportunistic infections. Marijuana use is a risk factor for
Mycobacterium tuberculosis (TB) infections [75–77]; this author speculates the suppression of host
innate immune responses by THC contributes to the increased severity of TB in users. Similarly, more
serious exacerbations central nervous system infection by Acanthamoeba among HIV-infected patients
has been attributed to marijuana consumption [78], possibly by inhibiting macrophage chemotaxis [79].
However, the antiinflammatory effects of cannabinoids have been found to be beneficial in attenuating
fever induced by bacterial endotoxin [65,80], inhibiting cytokine responses to Corynebacterium
parvum endotoxin [81]. These drugs may also offer therapeutic efficacy in meningitis caused by
Streptococcus pneumoniae [82] and in irritable bowel syndrome [83,84].
Cannabinoids may relieve pain and may induce hyperphagia, which could be beneficial in
cancer [85,86]. However, these physiological characteristics are not relevant to most viral, bacterial
fungal or parasitic infections, where the regulation of inflammation is central to controlling pathogen
replication and immunopathology. However, the same anti-inflammatory properties of cannabinoids
just described are detrimental to the host in handling the other infections. In most cases, a rapid and
robust inflammatory response, associated with production of proinflammatory cytokines and effect T
lymphocytes capable of eliminating infected cells is essential to recovery and survival.
3. Conclusions
Cannabinoids are profoundly anti-inflammatory and impair many Ca
2+
-dependent enzyme systems
which are central to inflammatory and cell-autonomous antiviral responses. When viral-induced host
responses lead to immunopathology, as is seen in a rodent model of multiple sclerosis, TMEV-IDD, or
in a persistent infection of the central nervous system caused by a non-lytic virus, BDV, cannabinoid
treatment was beneficial.
In all other virus infections, both in vitro and in vivo, cannabinoid treatment led to disease
progression, increased pathology, and sometimes to host death. Therefore, in many clinical settings,
including latent infections caused by HIV-1 or HSV-1, and persistent infection of the liver caused by
HCV, cannabinoids lead to worsened disease outcome.
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Acknowledgements
The generous support of the U.S. National Institutes of Health, both grants DC039746 and
NS039746, enabled my lab to perform these studies, and to summarize the work of many other labs.
Two former students, Ramon Antonio Herrera and Joseph H. Oved, contributed published [52] and
unpublished data, provided stimulating discussions and critically read this manuscript.
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ASTROCYTES are an important cell population in the CNS, involved in cytokine homeostasis and participating in a variety of important physiological and pathological processes. In the present study we showed that primary cultures of neonatal mouse cortical astrocytes stimulated with lipopolysaccharide (Balb/c mice strain, LPS: 1 mu g/ml, 18 h) or Theiler's virus, TMEV (SJL/J mice strain, TMEV: 10(5) PFU/well, 24h) released an increased amount of nitrites (NO2-) and tumour necrosis factor-alpha (TNF-alpha) into the culture medium. Exogenous cannabinoids are known to modulate the function of immune cells. Anandamide, an endogenous ligand for the cannabinoid receptor, blocked the release of NO2- and TNF-alpha induced by LPS in a dose-dependent manner. In TMEV-stimulated astrocytes anandamide also suppressed, in a dose-related manner, the stimulatory effects of TMEV on both NO2- and TNF-alpha. It is suggested that anandamide exerts an immunoregulatory role in the CNS. These results could have important implications in the modulation of immunological and inflammatory processes by cannabinoid agents.
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Adhesion molecules are critical players in the regulation of transmigration of blood leukocytes across the blood–brain barrier in multiple sclerosis (MS). Cannabinoids (CBs) are potential therapeutic agents in the treatment of MS, but the mechanisms involved are only partially known. Using a viral model of MS we observed that the cannabinoid agonist WIN55,212-2 administered at the time of virus infection suppresses intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in brain endothelium, together with a reduction in perivascular CD4+ T lymphocytes infiltrates and microglial responses. WIN55,212-2 also interferes with later progression of the disease by reducing symptomatology and neuroinflammation. In vitro data from brain endothelial cell cultures, provide the first evidence of a role of peroxisome proliferator-activated receptors gamma (PPARγ) in WIN55,212-2-induced downregulation of VCAM-1. This study highlights that inhibition of brain adhesion molecules by WIN55,212-2 might underline its therapeutic effects in MS models by targeting PPAR-γ receptors.
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Cannabinoids have recently been approved as a treatment for pain in multiple sclerosis (MS). Increasing evidence from animal studies suggests that this class of compounds could also prove efficient to fight neurodegeneration, demyelination, inflammation and autoimmune processes occurring in this pathology. However, the use of cannabinoids is limited by their psychoactive effects. In this context, potentiation of the endogenous cannabinoid signalling could represent a substitute to the use of exogenously administrated cannabinoid ligands. Here, we studied the expression of different elements of the endocannabinoid system in a chronic model of MS in mice. We first studied the expression of the two cannabinoid receptors, CB(1) and CB(2), as well as the putative intracellular cannabinoid receptor peroxisome proliferator-activated receptor-alpha. We observed an upregulation of CB(2), correlated to the production of proinflammatory cytokines, at 60 days after the onset of the MS model. At this time, the levels of the endocannabinoid, 2-arachidonoylglycerol, and of the anti-inflammatory anandamide congener, palmithoylethanolamide, were enhanced, without changes in the levels of anandamide. These changes were not due to differences in the expression of the degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, or of biosynthetic enzymes, diacylglycerol lipase-alpha and N-acylphosphatidylethanolamine phospholipase-D at this time (60 days). Finally, the exogenous administration of palmitoylethanolamide resulted in a reduction of motor disability in the animals subjected to this model of MS, accompanied by an anti-inflammatory effect. This study overall highlights the potential therapeutic effects of endocannabinoids in MS.
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Many virus infections elicit vigorous host immune responses, both innate and acquired. The immune responses are fre- quently successful in controlling and then clearing the virus, using both cellular effectors such as natural killer (NK) cells and cytolytic T lymphocytes and soluble factors such as inter- ferons (IFNs). However, some immune responses lead to pathologic changes or are unable to prevent the pathogen's growth. This review will not be devoted to the different strat- egies viruses have taken to promote their transmission or sur- vival but rather to one aspect of the innate immune response to infection: the role of nitric oxide (NO) in the antiviral reper- toire. Recently, data from many laboratories, using both RNA and DNA viruses in experimental systems, have implicated a role for NO in the immune response. The data do not indicate a magic bullet for all systems but suggest that NO may inhibit an early stage in viral replication and thus prevent viral spread, promoting viral clearance and recovery of the host. The earliest host responses to viral infections are nonspecific and involve the induction of cytokines, among them, IFNs and tumor necrosis factor alpha (TNF-a). Gamma IFN (IFN-g) and TNF-a have both been shown to be active in many cell types and induce cascades of downstream mediators (reviewed in references 25, 34, and 41). Others have found that NO synthase type 2 (NOS-2, iNOS) is an IFN-g-inducible protein in macrophages, requiring IRF-1 as a transcription factor (12, 17). We have observed that the isoform expressed in neurons, NOS-1, is IFN-g, TNF-a, and interleukin-12 (IL-12) inducible (20). Thus, NOS falls into the category of IFN-inducible pro- teins, activated during innate immune responses. NO is produced by the enzymatic modification of L-arginine to L-citrulline and requires many cofactors, including tetrahy- drobiopterine, calmodulin, NADPH, and O2. NO rapidly re- acts with proteins or with H2O2 to form ONOO 2 , peroxyni-