ArticlePDF AvailableLiterature Review

Abstract

Zinc is an essential trace element that is crucial for growth, development, and the maintenance of immune function. Its influence reaches all organs and cell types, representing an integral component of approximately 10% of the human proteome, and encompassing hundreds of key enzymes and transcription factors. Zinc deficiency is strikingly common, affecting up to a quarter of the population in developing countries, but also affecting distinct populations in the developed world as a result of lifestyle, age, and disease-mediated factors. Consequently, zinc status is a critical factor that can influence antiviral immunity, particularly as zinc-deficient populations are often most at risk of acquiring viral infections such as HIV or hepatitis C virus. This review summarizes current basic science and clinical evidence examining zinc as a direct antiviral, as well as a stimulant of antiviral immunity. An abundance of evidence has accumulated over the past 50 y to demonstrate the antiviral activity of zinc against a variety of viruses, and via numerous mechanisms. The therapeutic use of zinc for viral infections such as herpes simplex virus and the common cold has stemmed from these findings; however, there remains much to be learned regarding the antiviral mechanisms and clinical benefit of zinc supplementation as a preventative and therapeutic treatment for viral infections.
REVIEW
The Role of Zinc in Antiviral Immunity
ScottARead,
1,2Stephanie Obeid,3Chantelle Ahlenstiel,3andGoloAhlenstiel
1,2
1Blacktown Medical School, Western Sydney University, Blacktown, New South Wales, Australia; 2Storr Liver Centre, The Westmead Institute for Medical
Research, The University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia; and 3The Kirby Institute, University of New South Wales,
Sydney, New South Wales, Australia
ABSTRACT
Zinc is an essential trace element that is crucial for growth, development, and the maintenance of immune function. Its influence reaches all organs
and cell types, representing an integral component of approximately 10% of the human proteome, and encompassing hundreds of key enzymes
and transcription factors. Zinc deficiency is strikingly common, affecting up to a quarter of the population in developing countries, but also affecting
distinct populations in the developed world as a result of lifestyle, age, and disease-mediated factors. Consequently, zinc status is a critical factor that
can influence antiviral immunity, particularly as zinc-deficient populations are often most at risk of acquiring viral infections such as HIV or hepatitis
C virus. This review summarizes current basic science and clinical evidence examining zinc as a direct antiviral, as well as a stimulant of antiviral
immunity. An abundance of evidence has accumulated over the past 50 y to demonstrate the antiviral activity of zinc against a variety of viruses,
and via numerous mechanisms. The therapeutic use of zinc for viral infections such as herpes simplex virus and the common cold has stemmed
from these findings; however, there remains much to be learned regarding the antiviral mechanisms and clinical benefit of zinc supplementation
as a preventative and therapeutic treatment for viral infections. Adv Nutr 2019;0:1–15.
Keywords: zinc, virus, metallothionein, antiviral, immunity, zinc deficiency, zinc supplementation
Introduction
Zinc deciency was rst recognized by Prasad et al. >50 y
ago in a malnourished group of individuals presenting
with hepatosplenomegaly, dwarsm, hypogonadism, and an
elevated risk of infection (1). Unbeknownst to Dr. Prasad and
his colleagues at the time, their discovery would highlight
the importance of zinc as an integral component of human
physiology, and inspire decades of zinc research. It is now
understood that zinc is the second-most abundant trace
metalinthehumanbodyafteriron,andanessentialcom-
ponent of protein structure and function. Importantly, zinc
is a structural constituent of 750 zinc-nger transcription
factors (2) enabling gene transcription, and is a catalytic
component of approximately 2000 enzymes, encompassing
all 6 classes (hydrolase, transferase, oxido-reductase, ligase,
lyase, and isomerase) (3). Hence, zinc is biologically essential
Supported by Sylvia and Charles Viertel Charitable Foundation Investigatorship (VTL2015C022).
Author disclosures: SAR, SO, CA, and GA, no conicts of interest.
Address correspondence to SAR (e-mail: s.read@westernsydney.edu.au).
Abbreviations used: EV, epidermodysplasia verruciformis; HCMV, human cytomegalovirus; HCV,
hepatitis C virus; HPV, human papilloma virus; HSV,herpes simplex virus; IRF, IFN regulatory
factor; ISG, interferon stimulated gene; MT, metallothionein isoforms; MTF1, metal-responsive
transcription factor; PRR, pattern recognition receptor; RdRp, RNA-dependent RNA polymerase;
RT, reverse transcriptase; SOCS, suppressors of cytokine signaling; TLR, Toll-like receptor; ZIP,
Zrt- and Irt-like proteins.
forcellularprocesses,includinggrowthanddevelopment,as
well as DNA synthesis and RNA transcription (4).
The global prevalence of zinc deciency is estimated
to range from 17% to 20% (5,6), with the vast ma-
jority occurring in developing countries of Africa and
Asia. Although signicantly less common in high-income
nations, zinc deciency occurs most frequently in the elderly,
vegans/vegetarians, and individuals with chronic disease
such as liver cirrhosis (7)orinammatoryboweldisease
(8). Importantly, zinc deciency results in a compromised
immune system, as evidenced by thymic atrophy, lymphope-
nia, and defective lymphocyte responses in animal studies
(9). These data underscore the importance of zinc nutrition,
particularly in underdeveloped countries where the risk of
infection is heightened because of poor sanitation, public
health, and vaccination strategies (5).
This review focuses on the role of zinc as an essential
micronutrient that is required to mount an eective antiviral
response. Although zinc possesses direct antiviral properties
(e.g. inuenza), it is also critical in generating both innate
and acquired (humoral) antiviral responses. To complicate
matters, zinc is an integral component of many viral enzymes,
proteases, and polymerases, highlighting the importance of
regulating cellular and systemic zinc distribution to inhibit
viral replication and dissemination.
Copyright C
American Society for Nutrition 2019. All rights reserved. Adv Nutr 2019;0:1–15; doi: https://doi.org/10.1093/advances/nmz013. 1
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
Current Status of Knowledge
Zinc homeostasis and viral infection
Systemic and intracellular zinc are tightly regulated, such
that free zinc ions (Zn2+) represent a minimal fraction of
total cellular zinc (0.0001%) (10–12). The vast majority
of zinc remains bound to zinc-binding proteins such as
serum albumin or intracellular metallothionein proteins,
where it can be transferred to zinc-binding enzymes and
transcription factors as necessary. Zinc transport is princi-
pally mediated by 2 groups of proteins: the ZnT [solute-
linked carrier 30 (SLC30A)] family, which is responsible
foreuxofzincoutsidethecellorinuxintoorganelles,
and the ZIP [Zrt- and Irt-like proteins (SLC39A)] family
of proteins, which performs the opposite role, transporting
zinc into the cytoplasm from extracellular sources or cellular
organelles (13). The >30 human proteins responsible for zinc
homeostasiscollectivelyensurethatzincdoesnotbecome
toxic in the case of dietary excess, nor limited in the case
of dietary insuciency. Of course, this balance cannot be
maintained indenitely, and may result in zinc-induced
copper deciency if consumed in excess (14), and severe zinc
deciency if it is lacking in the diet (1).
Sequestration and toxic accumulation of metals are well-
documented antibacterial immune responses. Calprotectin
is a prime example, binding and sequestering extracellular
calcium and zinc, thus preventing bacterial and fungal
overgrowth (15). Conversely, toxic endosomal zinc accu-
mulation can inhibit intracellular Mycobacterium growth in
macrophages (16). Unfortunately, these mechanisms are not
well described in the case of viral infections, perhaps because
of a lack of ecacy. Calprotectin, for example, has no proven
antiviral role, nor is it signicantly upregulated in response
to viral gastroenteritis (17). This absence of a zinc-mediated
antiviral response may reect the “parasitic” nature of viral
infection, hijacking host machinery to self-replicate. Changes
in intracellular zinc concentrations necessary to inhibit viral
replication may also prove toxic to eukaryotic cells for the
same reason.
Although antiviral modulation of zinc homeostasis in
humans remains unproven, papilloma viruses have evolved
mechanisms to alter zinc homeostasis to favor viral replica-
tion and persistence (18). The human papilloma virus (HPV)
E5 protein can interact with the zinc transporter ZnT-1 in
complex with EVER2, thus stimulating nuclear accumulation
of zinc (19). The ZnT-1:EVER2 complex responsible for zinc
export from the nucleus is inhibited by HPV E5, subsequently
increasing both nuclear zinc and the activation of AP1 (20),
a transcription factor required for HPV genome expression.
Interestingly, homozygous mutations in either EVER1 or
EVER2 result in a rare condition termed epidermodysplasia
verruciformis (EV).EVpatientsareparticularlysusceptibleto
HPV strains 5 and 8, which signicantly increases the risk of
developing nonmelanoma skin cancers. HPV strains 5 and 8
lack expression of the E5 protein, which may explain 1)their
limited replication in the normal population because of their
inability to control zinc homeostasis, and 2)thesusceptibility
of EV patients to strains 5 and 8 from the loss of EVER protein
function, favoring HPV replication. Interestingly, HPV E5
genes have co-evolved with the major HPV oncogenes, E6
and E7, and indicate the potential involvement of E5 in
carcinogenesis (21,22). Clinical trials using both oral and
topical zinc have proven eective for the treatment of viral
warts,andwillbereviewedinalatersection.
Metallothioneins, zinc homeostasis, and antiviral activity.
Metallothioneins are small, cysteine-rich proteins capable
of binding divalent cations such as zinc and copper. As
vessels for much of the labile intracellular zinc pool,
metallothioneins possess numerous functions through their
ability to bind and release metals from their thiol groups.
These include storage and transfer of zinc ions and heavy
metal detoxication, as well as involvement in oxidative
stress, apoptosis, and immune responses (23). Humans
express 4 metallothionein isoforms (MT1–4), including the
ubiquitously expressed MT1 and MT2 genes (MT1A, B,
E, F, G, H, I, J, L, M, X, MT2A), as well as MT3 and
MT4 whose expression is limited, and function remains
poorly understood (24). Importantly, MT1 and 2 gene
expression is extremely responsive to zinc, and therefore
serves as an ideal indicator of an individual’s zinc status (25).
Upon taking a zinc supplement, for example, an increase
in protein-bound zinc in the bloodstream is internalized
by cells in various tissues and organs through the ZIP
transporters. In response to increased intracellular zinc,
the metal-responsive transcription factor (MTF1) becomes
active, and binds the metal responsive element in metal-
lothionein gene promoters to upregulate their transcription
(26). Although there are additional stimuli that inuence
metallothionein expression, this primarily occurs in a zinc-
dependent fashion. Oxidative stress, for example, induces
zinc release from metallothioneins as a mechanism to reduce
reactive oxygen species generated by mitochondrial dysfunc-
tion or viral infection (26). Zinc released from metalloth-
ioneins binds MTF1 to stimulate additional metallothionein
expression.
It should be noted that metallothioneins, although highly
responsive to zinc, have long been classied as interferon
stimulated genes (ISGs) (27). IFNs are immunostimulatory
cytokines secreted from infected cells and nearby immune
cells that induce the expression of hundreds of antiviral
genes. They possess diverse roles including chemoattraction,
immune cell activation, and direct antiviral activity. In
responsetoIFNs,wesuggestthatthereare2mechanismsof
metallothionein induction. Most ISGs possess binding sites
for STAT- or IFN regulatory factor (IRF) transcription factor-
mediated expression, as is the case for MT1X and MT2A (28,
29). Other metallothioneins such as MT1F and MT1G do not
possess known IFN regulatory regions in their promoters,
but are instead more sensitive to zinc (28). IFNs stimulate
an inux of zinc into the target cell, as is the case with some
inammatory cytokines such as IL-6, which in turn drives
metallothionein expression.
2Readetal.
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
Because metallothioneins possess such a diverse func-
tional repertoire, their specic roles during viral infection
remain undened. However, both in vitro and in vivo
studies have made it abundantly clear that metallothioneins
are induced by viruses. The mechanisms often remain
undened; however, metallothionein expression has been
attributed to zinc inux or redistribution (19,28), by
viral means, cytokine exposure, or oxidative stress (30).
Metallothionein upregulation has been observed in response
to measles virus (31), inuenza (31,32), HIV (33), hepatitis
Cvirus(HCV)(34), and coxsackie virus (35), among others.
In the case of HIV, zinc appears to be the key driver of
metallothionein expression to favor viral persistence. HIV-
infected monocytes demonstrate a signicant increase in
both MT1 gene expression as well as intracellular zinc (33).
Elevated intracellular zinc increases monocyte resistance to
apoptosis via inhibition of caspase 3 activation [as has been
reported previously (36)], thus providing a reservoir for HIV
replication. The role of metallothioneins remains unclear in
this study; however, they have been described as negative
regulators of apoptosis, albeit not through direct caspase
3inhibition(37). Zinc and metallothioneins also facilitate
human cytomegalovirus (HCMV) replication by activating
the immediate-early HCMV promoter (38,39). Kanekiyo et
al. demonstrated that both zinc and metallothionein overex-
pression increased NF-κB binding in the HCMV promoter.
Because no complex was detected between metallothionein
and NF-κB, it was suggested that metallothioneins served
as a zinc donor necessary for NF-κB binding. In addition,
as NF-κB transcription factors are known potent activators
of HIV and HSV replication, and several other viruses
(40), metallothioneins may be proviral. Zinc has also been
reported to inhibit NF-κB in numerous studies (41–43).
Despite these contrasting data, Kim et al. have bridged these
inconsistencies, demonstrating that MT2A can serve as a sink
for excess zinc (44), thus limiting its proximity to NF-κBand
favoring NF-κB-mediated transcription.
In the case of HCV infection, metallothioneins possess
an antiviral role. Using a pan-metallothionein siRNA to
knockdown all MT1 and 2 genes, we demonstrated both an
increase in HCV replication and a decrease in intracellular
zinc content in vitro (34). Interestingly, although ZnSO4can
reduce HCV replication, this eect was ablated when metal-
lothionein genes were knocked down. These data suggest that
metallothioneins are either 1) directly antiviral, potentially
by sequestering zinc away from viral metalloproteins such
as HCV NS5A (45), or 2) indirectly antiviral by acting as
zinc chaperones and facilitating antiviral signaling. Further,
metallothioneins possess antiviral properties against other
viruses as well, as demonstrated in an antiviral screen
of 380 human ISGs performed by Schoggins et al. (46).
Overexpression of multiple members of the MT1 family
inhibited replication of aviviruses including yellow fever
virus and HCV, as well as the alphavirus Venezuelan equine
encephalitis virus. This eect was not observed in West
Nile virus, and Chikungunya virus. These data indicate that
metallothioneins, like many ISGs, are selectively antiviral,
perhaps reecting specic viral zinc requirements during
replication. This is particularly evident for HIV, which
demonstrated an increase in viral replication as a result of
metallothionein overexpression in the Schoggins et al. ISG
screen (46), validating previous works (33).
Zinc as an antiviral: bench to bedside and back again
Manystudieshaveevaluatedtheecacyofzincasan
antiviral agent in vitro. Unfortunately, zinc concentrations
used to assess antiviral activity often far exceed physiological
concentrations. Human plasma zinc, for example, ranges
from approximately 10 to 18 μM(47), whereas antiviral
concentrations of zinc can reach into mM concentrations
(48). Intracellular zinc concentrations range from 10s to 100s
of μM, but are signicantly buered by zinc-binding proteins
such as metallothioneins, rendering free zinc concentrations
at picomolar to low nanomolar concentrations (49,50). The
antiviral properties of zinc are certainly virus-specic, but
it would appear that zinc ion availability plays a signicant
role in the antiviral ecacy of zinc (51). Here we describe
the role of zinc as a virus-specic antiviral: both in vitro
mechanistic studies, as well as human-based clinical trials
using zinc supplementation. In vitro and in vivo studies are
summarized in Tab l es 1 and 2,respectively.
Herpesviridae.
The eect of zinc on HSV-1 and -2 has been studied for >40 y,
with in vitro studies suggesting that zinc plays an inhibitory
role on almost every aspect of the viral life cycle: viral
polymerase function (52),proteinproductionandprocessing
(53), and free virus inactivation (48,54). Although these
studies were performed >20 y ago, a more recent study using
the zinc ionophore pyrithione demonstrated a reduction
in HSV replication from reduced NF-κBactivationby
interfering with the protein ubiquitination pathway (41).
Unfortunately, no recent experimental data can demonstrate
with any certainty the mechanism by which zinc inhibits
HSV infection. Nonetheless, in vivo studies in mice and
humans have shown a signicant reduction of infection and
disease burden. Mouse studies performing intravaginal zinc
inoculation in liquid (55)orgel(56)formbothresulted
in signicant reductions in HSV-2 infection. Several topical
zinc application studies have been performed in humans,
which demonstrated a signicantly reduced recurrence and
duration of infection (outbreak) (5758). The ecacy of
topical application, together with in vitro results (48,54),
suggest that free zinc may indeed coat HSV virions, thus
preventing infection. Further research into this molecular
mechanism is warranted.
Apart from HCMV mentioned above, the eect of zinc
on other members of the Herpesviridae family remains
unknown because of a lack of clinical data. Mechanistically,
zinc ions have been shown to inhibit Varicella-Zoster virus by
inactivating free virus in vitro (59). Both HSV and Varicella-
Zoster virus belong to the Alphaherpesvirinae subfamily,
reecting their genetic relatedness, and similar mechanism
of inhibition.
Zinc as an antiviral 3
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
TABLE 1 In vitro studies assessing the antiviral ecacy of zinc1
Virus Antiviral effect Zinc Effective dose Reference
Coronavirus Inhibition of RdRp template binding and elongation PT +Zn(OAc)22–320 μMPT+2–500 μMZn (60)
Encephalomyocarditis virus Inhibition of viral polyprotein cleavage ZnCl20.4–1.5 mM (61)
Inhibition of viral polyprotein cleavage ZnCl20.1–1 mM (62)
Inhibition of viral polyprotein tertiary structure PT, HK 5–20 μM PT, 60–125 μMHK (63)
Inhibition of viral polyprotein tertiary structure PDTC 15–125 μMPDTC (63)
Foot and mouth disease virus Inhibition of viral polyprotein cleavage ZnCl2,Zn(OAc)
20.1–2 mM (64)
Inhibition of viral RNA and procapsid synthesis ZnCl210–150 μM(65)
Hepatitis C virus Inhibition of RNA polymerase ZnCl260–300 μM(66)
Inhibition of viral replication ZnCl2,ZnSO
450–150 μM(67)
Metallothionein-dependent inhibition of viral replication ZnSO450 μM(34)
Herpes simplex virus Viral protein synthesis ZnSO4N/A (53)
Inhibition of viral DNA polymerase Zn(OAc)20.1–2 mM (52)
Free virus inactivation ZnSO40.1–6 mM (48)
Free virus inactivation Zn(Glu)2, Zn(Lac)21–50 mM (54)
Inhibition of protein ubiquitination and NF-κB activity PT 1.2–18.9 mM (41)
Human immunodeficiency virus HIV protease inhibition Not listed 0.2–2 mM (68)
Inhibition of viral transcription and particle production ZnCl270–700 μM(69)
Inhibition of reverse transcriptase ZnCl225–800 μM(70)
Human papilloma virus Stimulates proviral transcription factor activity, reversed
by EVER2
N/A N/A (19)
Inhibition of viral protein E6 and E7 synthesis stimulating
apoptosis
CIZAR 500–750 μM(71)
Respiratory syncytial virus Reduction in viral titer and plaque count ZnCl2,Zn(OAc)
2, Zn(Lac)20.01–10 mM (72)
Rhinovirus Inhibition of viral polyprotein cleavage ZnCl2100–800 μM(73,74)
Inhibition of viral polyprotein cleavage ZnCl20.1–1.2 mM (61)
Inhibition of viral polymerase not listed >0.6 μM(75)
Inhibition of viral polyprotein processing PT, HK 5–20 μM PT, 60–125 μMHK (63)
Inhibition of viral polyprotein processing PDTC 15–125 μMPDTC (63)
Semliki Forest virus Inhibition of endosomal membrane fusion ZnCl225–100 μM(76)
Inhibition of endosomal membrane fusion ZnCl22mM (77)
Sindbis virus Inhibition of viral particle production and polyprotein
cleavage
ZnCl20.1–1.8 mM (78)
Transmissible gastroenteritis virus Inhibition of viral RNA and protein synthesis ZnCl2,ZnSO
410–200 μM(79)
Vaccinia virus Inhibition of RNA synthesis and viral yield ZnSO4100–300 μM(80)
Inhibition of viral particle production and polyprotein
cleavage
ZnCl250–400 μM(81)
Inhibition of viral topoisomerase Not listed 2.5 mM (82)
Varicella-zoster virus Free virus inactivation Zn(Pic)2,Zn(Asp)
210 μM(59)
1CIZAR, zinc citrate compound; HK, hinokitiol; N/A, not applicable; PDTC, pyrrolidine-dithiocarbamate; PT, pyrithione; RdRp, RNA-dependent RNA polymerate; Zn(Asp)2, zinc aspartate; ZnCl2, zinc chloride; Zn(Glu)2, zinc gluconate; Zn(Lac)2,zinc
lactate; Zn(OAc)2, zinc acetate; Zn(Pic)2, zinc picolinate; ZnSO4, zinc sulfate.
4Readetal.
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
TABLE 2 Human clinical studies using zinc as an antiviral therapy 1
Viral infection/condition Antiviral/therapeutic effect Effective dose Treatment Reference
Torque teno virus Reduced viral load following stem cell transplant 600 mg ZnSO4/d Oral (83)
Herpes simplex Reduced duration and severity of outbreak ZnO/glycine cream (0.3% ionic Zn) Topical (57)
Reduction in outbreak recurrence 0.025% ZnSO4solution Topical (84)
Reduction in outbreak recurrence 1–4% ZnSO4solution Topical (58)
Experimental rhinovirus Reduced duration of illness with Zn(Glu)2only Zn(Glu)2(13.3 mg) or Zn(OAc)2(5/11.5 mg) lozenges, every 2–3 h/d Lozenge (85)
Common cold Reduced symptom severity, frequency, and duration ZGG lozenges containing 23 mg Zn, every 2 h/d Lozenge (86)
Reduced symptom severity, frequency, and duration ZGG lozenges containing 24 mg Zn, every 2–3 h/d (Max 8) Lozenge (87)
Reduced duration of symptoms ZGG lozenges containing 13 mg Zn, every 2 h/d Lozenge (88)
Reduced symptom severity and duration Zn(OAc)2lozenges each containing 9 mg Zn, every 2 h/d Lozenge (89)
Reduced symptom severity and duration Zn(OAc)2lozenges each containing 13 mg Zn, every 2–3 h/d Lozenge (90)
No effect on duration or severity Zn(Glu)2(13.3 mg) or Zn(OAc)2(5/11.5 mg) lozenges, every 2–3 h/d Lozenge (85)
Reduced symptom severity and duration Zn(OAc)2lozenges each containing 13 mg Zn, every 2–3 h/d Lozenge (91)
Viral warts Improved clearance of warts after 1–2 mo 10 mg/ kg ZnSO4to a maximum dose of 600 mg/d Oral (92)
Clearance of warts based on concentration of zinc used 3 ×5 or 10% ZnSO4/d Topical (93)
Improved clearance of warts after 1–2 mo 10 mg/ kg ZnSO4to a maximum dose of 600 mg/d Oral (94)
No benefit 10 mg/ kg ZnSO4/d Oral (95)
Resolution of 88% of lesions after 6 wk/3 sessions Up to 3 intralesional injections with 2% ZnSO4Injection (96)
Laryngeal papillomatosis Resolution of papillomatosis (2 case studies) 10 mg/ kg ZnSO4/d Oral (97)
HIV Reduced infection, increased CD4 T cell count 200 mg/d ZnSO4/d Oral (98)
Increased CD4 T cell count 45 mg Zn(Glu)2every8hfor15d,then15mgfor15d Oral (99)
Reduced incidence of diarrhea 10 mg elemental zinc as ZnSO4/d Oral (100)
No benefit 25 mg/d ZnSO4/d Oral (101)
Chronic hepatitis C virus Enhanced response to IFN treatment 2 ×75 mg polaprezinc/d Oral (102)
No benefit to IFN treatment response 5 ×78 mg Zn(Glu)2/d Oral (103)
Reduced serum AST, ALT, and ferritin 3 ×75 mg polaprezinc/d Oral (104)
Reduced serum ALT and Th2 cells (%) 2 ×75 mg polaprezinc/d Oral (105)
Reduced incidence of HCC (albumin-dependent) 2 ×150 mg polaprezinc/d Oral (106)
1ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCC, hepatocellular carcinoma; ZGG, zinc gluconate/glycine; Zn(Glu)2, zinc gluconate; ZnO, zinc oxide; Zn(OAc)2,zincacetate;ZnSO
4, zinc sulfate.
Zinc as an antiviral 5
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
Picornaviridae.
It was clear as early as 1974 that zinc possessed an inhibitory
eect on picornovirus polyprotein processing (73). Before
1980, zinc inhibition of picornovirus proteases from human
rhinovirus isolates (73,74), encephalomyocarditis virus (62),
poliovirus (61), and foot and mouth disease virus (64,65)
had all been demonstrated. More recent studies using zinc
ionophores have illustrated that zinc interferes with the
autocatalytic processing of the viral protease 3CDpro into
3Cpro in the picornavirus coxsackievirus B3, thus inhibiting
processing of the viral polyprotein (107). However, this was
not the case for encephalomyocarditis virus, where zinc
appeared to inhibit the tertiary structure within the viral
polyprotein (107). Together, these data suggest that zinc may
interfere with proteolytic processing of the viral polyprotein
because of misfolding, or through direct actions on the viral
protease 3CDpro.
Clinical studies using zinc supplementation are primarily
limited to rhinovirus infection, and are often grouped
with other “common cold” viruses such as inuenza and
coronaviruses. The majority of studies use zinc lozenges with
various zinc formulations and concentrations, possibly ex-
plaining the large variability in results [extensively reviewed
in (108)and(109)]. Importantly, the amount of ionic zinc
present at the site of infection (oral and nasal mucosa) is
highly correlated to the study outcome (51,108), and is
dependent on the zinc formulation. At a physiological pH
and 37C, zinc gluconate for example, releases high amounts
of ionic zinc, whereas zinc aspartate releases none (108).
Upon examining only the relevant studies where high doses
of ionic zinc were used, a clear reduction in cold duration
of 42% was calculated (109). Whether this was caused by
viral inhibition, improved local immune response, or an
amelioration of symptoms remains uncertain.
Other respiratory tract infections: inuenza, coronavirus,
and metapneumovirus.
Few studies have examined the antiviral eects of zinc on
other respiratory viruses. In vitro replication of inuenza
(PR/8/34) is signicantly inhibited by the addition of the
zinc ionophore pyrrolidine dithiocarbamate (110), perhaps
through inhibition of the RNA-dependent RNA polymerase
(RdRp), as had been suggested 30 y earlier (111). In similar
fashion, severe acute respiratory syndrome (SARS) coron-
avirus RdRp template binding and elongation was inhibited
by zinc in Vero-E6 cells (60). Moreover, zinc salts were shown
to inhibit respiratory syncytial virus, even while zinc was
incubatedwithHEp-2cellsonlybeforeinfection,andthen
removed (72). The authors suggest that this indicates an
inhibitory mechanism similar to HSV by preventing viral
membrane fusion; however, no measures were taken to assess
changes in intracellular zinc content, nor inhibition of other
aspects of the viral life cycle.
Flaviviridae: a focus on HCV.
Flaviviruses represent a number of insect-borne viruses
including dengue and West Nile virus, as well as the
hepatotrophic virus, HCV. The eect of zinc on insect-borne
aviviruses is scarce; however, in vitro studies by our group
(34)andothers(67) have demonstrated that zinc salts can
reduce HCV replication (50% at 100 μMZnSO
4), perhaps
by inhibiting the HCV RdRp, as shown in E. coli [half
maximal inhibitory concentration (IC50) 60 μM] (66).
Although this is a potential mechanism, it has not been
examined in eukaryotic cells in which zinc homeostasis is
signicantly dierent.
If left untreated, HCV becomes a chronic hepatic infection
in around two-thirds of individuals (112), resulting in a
signicant reduction in plasma zinc (113). Consequently,
zinc supplementation in HCV studies have focused on
improved patient outcomes, particularly decreased liver
inammation, and enhanced response to antiviral treatment.
Supplementation with 150 mg/d polaprezinc (a bioavailable
zinc-carnosinechelate)hasbeenshowntoreducemarkers
of hepatic inammation alanine aminotransferase and aspar-
tate aminotransferase alone (105),andincombinationwith
the antiviral treatment IFN-α(106). Moreover, polaprezinc
signicantly improved the rate of viral clearance, particularly
in patients with lower viral loads at baseline (102). The
mechanisms underlying these observations remain uncer-
tain; however, are likely a combination of direct antiviral
eects and strengthening of the antiviral response. Zinc
supplementation and the antiviral response is reviewed
below.
Togav i ri d a e.
Like aviviruses, togaviruses primarily consist of arthropod-
borne viruses such as Semliki Forest virus, Western equine
encephalitis virus, and Chikungunya virus. Viral infection
occurs by receptor-mediated endocytosis, followed by fusion
of virus and endosomal membranes, and particle release
into the cytoplasm (114). Using liposome (76), red blood
cell (115), and BHK-21 (77) cell model systems, zinc has
been shown to eciently inhibit membrane fusion of Semliki
Forestvirusandsindbisviruses.Zincionsinterferewith
membrane fusion by binding to a specic histidine residue
revealed on the viral E1 protein at low endosomal pH (77).
Unfortunately,theinvivorelevanceofthismodelisunclear
becauseofthehighconcentrationofzinc(>1mM)used.
Notably, concentrated zinc is present in vesicular zincosomes
that are thought to serve as intracellular zinc storage vesicles
(116).Similartothemechanismusedbymacrophagesto
inhibit intracellular Mycobacterium spp., zincosome fusion to
viral endosomes may inhibit key aspects of the viral life cycle
such as togavirus membrane fusion.
Retroviridae: HIV.
Retroviruses are named after their ability to transcribe RNA
into DNA using their unique reverse transcriptase (RT),
consequently allowing integration of retroviral DNA into
the host genome. The integrated provirus can then establish
a latent infection for the life of the host and is a major
barrier to virus cure strategies, particularly for HIV-1 (117).
Similar to viral RdRps, zinc has also been identied as
6Readetal.
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
an inhibitor of retrovirus RTs (118,119). Fenstermacher
and DeStefano demonstrated in 2011 that Zn2+cations
candisplaceMg
2+ions from HIV-1 RT, promoting the
formation of an excessively stable, but incredibly slow and
inecient replication complex (70). Zinc was also shown
to inhibit the HIV-1 protease in 1991 (68), and to inhibit
viral transcription in 1999 (69), but has received little
attention since, with the exception of molecular simulation
experiments that identied the zinc-binding sites at the
catalytic aspartate-25 residue (120). As stated above, HIV can
also stimulate zinc inux into monocytes (33), which may
appear contradictory based on its antiretroviral properties.
Latently infected monocytes and macrophages, however, can
act as viral reservoirs for HIV (121), and could therefore
benet from zinc-mediated inhibition of cell death. In fact,
unlike the majority of CD4+T cells, low levels of replication
in macrophages do not result in cell death (122), making
them a viable reservoir, in addition to long-lived resting
CD4+T cells, for viral recrudescence after cessation of
antiretroviral treatment.
Zinc deciency is common in HIV-infected individuals,
where it is associated with inammation (123), immunologi-
cal failure (124), and death (125). A recent Cochrane Review
examined the role of micronutrient supplementation in
people living with HIV (126). Although a number of studies
demonstrated benecial eects of zinc supplementation,
the majority were underpowered. The authors concluded
that zinc supplementation probably increases blood zinc
concentration (moderate certainty), and may increase CD4+
counts (low certainty).
Unlike zinc supplements, prophylactic zinc gels have
shown a substantial benet to limit HIV infection in vivo.
Complete protection against vaginal SHIV-RT (a simian
HIV virus expressing the human RT) infection in macaques
was obtained by pretreating animals with an antiviral gel
containing 14 mM zinc acetate and 50 μM MIV-150, a reverse
transcriptase inhibitor (127). When used alone, zinc acetate is
a potent antiviral, providing 66% protection against SHIV-RT
vaginal infection (56)andanEC50<100 μMinperipheral
blood mononuclear cells against a range of HIV strains
(128). Importantly, zinc treatment did not aect viral titers
in macaques that became infected, nor did it result in zinc
resistant HIV mutants with conserved pol (RT) mutations.
These data suggest that zinc may not interfere with the
HIV RT, but instead inactivate free virus or prevent viral
attachment/penetration as reported for HSV (48,54).
Papillomaviridae.
HPVs are oncogenic viruses that infect basal epithelial
cells, where they stimulate proliferation resulting in warts.
Although cutaneous warts are usually self-limiting and
harmless, mucosal strains of HPV (e.g. high risk HPV-16
and -18) are a primary cause of cervical cancers (129).
HPV oncoproteins E6 and E7 in particular, are signicant
drivers of cell proliferation and resistance to cell death by
stimulating the degradation of tumor suppressor p53 and
pRb, respectively [reviewed in (130)]. Although nuclear zinc
appears to enhance HPV replication (see Zinc homeostasis
and viral infection), exogenous zinc treatment (CIZAR, zinc
chloride and citric acid anhydrous) can eectively inhibit
production of viral oncogenic proteins E6 and E7 (71). The
inhibition of E6 and E7 by zinc results in apoptosis of
cervical carcinoma cells, as they regain the function of tumor
suppressors p53 and pRb (71). The mechanism by which zinc
downregulates E6 and E7 expression is unknown, but may be
preceded by a zinc-driven blockade in another component of
the viral life cycle.
It would appear that both topical and oral zinc supple-
mentation strategies have proven tremendously eective for
cutaneous and genital warts. Unfortunately, the vast majority
of studies are either underpowered, lacking suitable controls,
or single case studies. Nonetheless, a recent systematic review
concluded that zinc supplementation was the most eective
systemic treatment for cutaneous warts, when compared to
other available options (131). It should be noted, however,
that individuals with persistent viral warts are often zinc-
decient or have lower concentrations than their healthy
counterparts (132). In fact, studies demonstrating the most
signicant responses to zinc treatment had engaged patients
that were primarily zinc-decient (>70 μg/dL) (92,94).
Nonetheless, 78% (94) and 100% (92)ofpatientsshowed
clearance of lesions in response to oral zinc sulfate (10 mg/kg
up to 600 mg/d) compared to 13% and 0% of the placebo
group, respectively. Topical zinc formulations have also
proved ecacious for treatment of viral warts. A small study
using a 4-wk topical 10% zinc sulfate regimen for plane warts
demonstrated an 86% response rate (6/7), compared to a 10%
response rate (1/10) in the control group (93).
Recent work suggests that treatment of vaginal HPV
infections with topical zinc formulations may benet the
millionsofwomenthatremainunvaccinatedagainstHPV.
A recent pilot study demonstrated that intravaginal infusion
of 500 μM zinc citrate in women diagnosed with high-risk
HPV resulted in a 64% clearance rate, compared to 15%
in the control group (133). Additional studies in mice have
demonstrated that MZC, a formulation containing MIV-50,
zinc acetate, and carrageenan, eciently inhibited vaginal
and anorectal HPV-16 pseudoviral particle infection (134).
In summary, it is evident that zinc possesses antiviral
properties against a number of viral species. Although
mechanistic studies are lacking, zinc appears to inhibit viral
protease and polymerase enzymatic processes, as well as
physical processes such as virus attachment, infection, and
uncoating (Figure 1). Unfortunately, these mechanisms have
not been well scrutinized in clinical studies, where zinc
may provide inexpensive and eective adjunct treatments for
many viral infections.
The role of zinc in antiviral immune signaling
Ionic zinc possesses unique and distinct antiviral properties
against a number of human viruses; however, the antiviral
immune response led by IFNs is invariably required to clear
infections. Zinc has been shown to contribute to a number
ofinnateandadaptiveimmunesignalingpathwaysthathave
Zinc as an antiviral 7
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
FIGURE 1 The diverse stages of viral replication cycles that are inhibited by zinc. In vitro studies have demonstrated a number of
mechanisms by which zinc interferes with the viral replication cycle. These include free virus inactivation (1), inhibition of viral uncoating
(2), viral genome transcription (3), and viral protein translation and polyprotein processing (4). No studies to date, however, have
demonstrated zinc-mediated inhibition of virus assembly and/or particle release. CV, coronavirus; DdDp, DNA-dependent DNA
polymerase; EMCV, encephalomyocarditis virus; FMDV, foot and mouth disease virus; HCV, hepatitis C virus; HIV, human immunodeficiency
virus; HPV, human papilloma virus; HRV, human rhinovirus; HSV, herpes simplex virus; PV, polio virus; RdRp, RNA-dependent RNA
polymerase; RT, reverse transcriptase; SARS, severe acute respiratory syndrome coronavirus; SFV, Semliki Forest virus; SV, sindbis virus; VZV,
varicella-zoster virus; Zn, zinc.
been comprehensively reviewed recently (135). As such, this
review will focus specically on the role of zinc in the
immune response to viruses.
Viral infections are recognized by a number of innate
immune receptors termed pattern recognition receptors
(PRRs). These include the cell surface and endosomal Toll-
like receptors (TLRs), as well as a variety of cytosolic
PRRs such as RIGI, MDA5, and IFI16 that primarily bind
viral nucleic acids (136). Following ligand binding, PRRs
share a number of downstream signaling intermediates,
that ultimately activate both inammatory (NF-κB, AP1)
and innate immune (IRF1/3/7) transcription factors. These
transcription factors cooperate to induce expression of IFNs,
ofwhichthereare3types:typeI(IFN-αand IFN-β), type
II (IFN-γ), and type III (IFN-λs). Type I and III IFNs
activate very similar antiviral signaling pathways; however,
the type I IFN response is ubiquitous, whereas the type III
IFN response is limited to a subset of immune cells, as well
as epithelial cells of the liver, gastrointestinal, and pulmonary
tracts (137). Although both IFN types bind unique receptors,
they activate a common signaling cascade where STAT1
andSTAT2heterodimerizeandbindIRF9,followedby
translocation into the nucleus and subsequent binding of the
IFN-sensitive response element that is present in hundreds
of gene promoters. As stated previously, these ISGs possess
numerous roles including immune cell chemotaxis and
activation, as well as numerous antiviral mechanisms to
inhibit viral replication within infected and neighboring cells.
Zinc and pathogen recognition.
Upon recognition of microbial antigens by TLRs, a rapid
and transient inux of free zinc ions occurs. Interestingly,
this has been demonstrated in response to viral stimuli,
imiquimod, ssRNA40 (TLR7), and CpG (TLR9), but not
polyI: C (TLR3) in the mouse macrophage RAW 264.7 cell
line (138). In response to TLR7 activation, zinc was shown
to reduce the production of type I IFNs and ISGs CD80
8Readetal.
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
and CD86. Based on results using other stimuli, the authors
suggest that zinc can inhibit IRF3-, and perhaps IRF7-
dependent IFNB production, by limiting activation and/or
nuclear translocation (138). The role of the zinc inux in
this context remains undened, but may reect a regulatory
mechanism to prevent excessive IFN production.
Although no direct inhibition of IRF signaling by zinc has
been demonstrated, zinc can modulate a number of factors
upstream of IRF activation. For example, the IκBkinase
(IKK) members IKKαand IKKβareinhibitedbyzinc,albeit
at high concentrations of 0.5 μM(139). IKKαhas been
shown to activate IRF7 in response to TLR7/9 stimulation
(140), whereas IKKβ(141), IKKεand TANK-binding kinase-
1 (TBK1) (142) can activate IRF3 following TLR3 stimuli.
Zinc can also stimulate expression of the deubiquitinating
enzyme A20 (43)toinhibitthepathogenresponse.A20
is a regulator of NF-κB- (143), TLR3- (144), and RIGI-
mediated (145) IFN production, most likely by targeting
PRR signaling components TIR-domain-containing adapter-
inducing interferon-β(TRIF), TNF Receptor Associated
Factor (TRAF) 2, and TRAF6. A20-decient cells are hyper-
responsive to viral infection, possess increased activation of
NF-κB, IRF3, and IRF7, and improved viral clearance (146).
Zinc and the interferon response.
After pathogen recognition, NF-κB, AP1, and IRF3/7 bind
IFN promoters to stimulate type I/III IFN production. Zinc
plays a signicant role in the response to IFNs by modulating
secretion, cytokine potency, and receptor binding, as well as
inuencing signaling intermediates and pathway inhibitors.
A recent study has demonstrated that intracellular zinc
can reduce IFN secretion by destabilizing sortilin mRNA
transcripts (147). Sortilin is an endosomal protein that
facilitates secretion of cytokines such as IFN-γand IL6 (148),
and its depletion results in a signicant reduction in secretion
of IFN-α. Consequently, because sortilin ensures tracking
and secretion of numerous cytokines, it is possible that zinc
also inhibits the secretion of other IFNs.
Structural studies have demonstrated that zinc ions can
mediate dimerization of IFNA molecules (149). Nonetheless,
apartfromcrystallizationstudies,dimersweredicultto
generate despite using concentrated IFN (50 μM) and zinc
(1 mM). It is therefore likely that the circulating active
form of IFN-αis monomeric. A single study performed in
2001 showed that zinc can increase the antiviral activity of
IFN-α10-fold against rhinovirus challenge (150). Although
this study drew radical conclusions, antiviral activity was
basedoncytopathiceectalone,anditsresultshavenot
been reproduced since. Moreover, zinc was added before
viral infection, which is known to interfere with rhinovirus
polyprotein processing (73,74), as reviewed above.
UnliketypeIIFNs,arecentstudybyourgrouphas
shown that zinc can inhibit IFN-λ3signaling,mostlikelyby
preventing receptor binding and subsequent signaling (28).
Upon demonstrating in 2014 that metallothionein expression
was IFNL genotype-dependent, and inversely associated
with ISG expression in HCV (151), we showed that serum
zinc was the driver of hepatic metallothionein expression.
Although zinc had minimal eect on IFN-αsignaling, it
could almost ablate IFN-λ3 signaling at a concentration of
50 μM, resulting in a signicant reduction in its antiviral
activity (28). Interestingly, we found no inhibition of IFN-
λ1activityusing50μMZnSO
4, suggesting a highly specic
interaction. The mechanism by which zinc interferes with
the IFN:receptor interaction remains uncertain; however, we
have ruled out an eect of zinc on IFN-λ3disuldebond
formation.
Type I and III IFNs bind to unique receptor complexes
composed of IFN-αreceptors IFNAR1/IFNAR2 and IFN-λ
receptors IFNLR1/IL10RB, respectively, but signal via almost
identical pathways. Consequently, zinc may act to reinforce
the shared IFN signaling cascade by inhibiting protein
tyrosine phosphatase enzymatic activity (152). Following
receptor engagement by IFNs, intracellular Janus protein
tyrosine kinases Jak1 and Tyk2 become phosphorylated,
which in turn phosphorylate STAT molecules to stimulate
ISG expression. By dephosphorylating these key signaling
molecules, a number of phosphatases have been shown to
“put the brakes” on IFN signaling. Phosphatases tyrosine-
protein phosphatase non-receptor type 6 (SHP1), type 11
(SHP2), and protein phosphatase 2A (PP2A) have all been
shown to inhibit JAK-STAT phosphorylation (153–155),
and are all inhibited by zinc ions, predominantly in the
nanomolar range (156–158). Interestingly, PP2A can also
inhibit the phosphorylation of IRF3, thus regulating antigen
recognition by PRRs (159). Conversely, the tumor suppressor
phosphatase and tensin homologue (PTEN) stimulates IRF3
activation by removing inhibitory phosphorylation at Ser97
(160), and is also inhibited by zinc at nanomolar concen-
trations (161). Zinc inhibits numerous pro- and antiviral
phosphatases, with the net eect on virus recognition and
response being undened, which clearly requires further
study.
To enable a highly controlled IFN response, negative
regulators of IFN signaling are often ISGs. These include
the suppressors of cytokine signaling (SOCS-1 and SOCS-
3), which bind and inhibit JAK protein signaling, thus
preventing signaling from numerous inammatory (IL-
6) and antiviral stimuli (162). Interestingly, zinc-driven
activation of the MTF-1 transcription factor can induce
expression of SOCS-3 in HepG2 cells (163). The zinc
importer ZIP-14, which is responsible for zinc inux
following inammatory stimuli, was required for SOCS-3
expression, and may represent yet another zinc-mediated
mechanism to limit the inammatory response. Although
the transporter responsible for hepatic zinc inux following
IFN stimulation remains unknown, it is perceivable that
ZIP-14 may drive zinc inux and subsequent SOCS-3
expression.
Zinc deficiency caused by disease, age, and lifestyle
factors: lessons from supplementation
Zinc status is primarily determined by dietary zinc intake;
however, additional factors such as dietary composition,
Zinc as an antiviral 9
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
alcohol intake, and disease state can signicantly reduce zinc
uptake and storage, or increase zinc excretion (164). With
respect to dietary composition, zinc supplementation as part
of a meal can signicantly reduce zinc absorption when
compared to water-based solutions of zinc (164). Moreover,
dietary phytate, a natural chelator of zinc ions that is present
in corn, rice, and cereals, can severely restrict zinc absorption
(165). Consequently, diets containing high phytate: zinc
molar ratios, can result in zinc deciency, even with adequate
zinc intake. Unfortunately, rural diets in low-income nations
are often zinc-poor and phytate-rich because of a dietary
reliance on rice and vegetables.
Aged individuals are also signicantly more susceptible to
zinc deciency, increasing their likelihood of acquiring life-
threatening viral infections (166). Ex vivo, zinc supplementa-
tion has been shown to improve leukocyte IFN-αproduction
(167) and to reduce mononuclear cell TNF production (168).
Year-long supplementation with 45 mg elemental zinc/d in
elderly subjects (aged 55–87 y), has also demonstrated a
dramatic reduction in the incidence of infection as well as
plasma oxidative stress markers (168).
Alcoholism can stimulate severe zinc deciency devel-
oped via numerous sociological and physiological mecha-
nisms, with factors including but not limited to 1)increased
urinary zinc excretion (169), 2) reduced zinc intake (poor
diet) (170), 3) reduced zinc absorption (171), and 4)anda
reductioninhepaticzincstores(172). Alcohol also stimulates
microbial dysbiosis and gastrointestinal permeability (173), a
phenotype that can increase the likelihood of viral infection
in the gut (174). Importantly, dietary zinc supplementation
can improve intestinal barrier dysfunction as a result of
alcohol and microbial infection (175,176).
As previously discussed, zinc deciency is common
among chronic infections such as HPV, HCV, and HIV (113,
123). Consequently, a number of studies have examined
the eects of zinc supplementation on antiviral immunity,
inammation, and treatment response. As described above,
zinc supplementation can improve HCV treatment response
and liver inammation caused by chronic infection. In
addition, long-term zinc treatment over 7 y has been shown
to reduce the risk of hepatocellular carcinoma progression in
chronic HCV patients, as assessed by multivariate analysis,
compared to controls (P<0.05) (105). Zinc supplementation
has also been assessed as an adjunct therapy to antiretroviral
administration in patients with HIV. One study reported
a4-foldreductionintherateofimmunefailure,aswellas
decreased diarrhea in patients treated with zinc compared
to controls (P<0.05 for both groups) (124). A more
recent study revealed an increase in CD4+Tcellcountin
patients treated with a combination of zinc and antiretroviral
therapy, compared to patients on antiretroviral therapy alone
(P<0.05) (177). Taken together, these data indicate that zinc
deciency is associated with greater disease activity in the
context of chronic viral infection. Oral zinc supplementation
may act in a synergistic manner when co-administered
with antiviral therapy and contribute to improved clinical
outcomes.
Vacc i n a t ion st u d ies .
Zinc supplementation during vaccination strategies has
provided an opportunity to examine the role of zinc in the
humoral response to viruses. A particular focus has been
applied to the eect of zinc supplementation on rotavirus
vaccination because of the high rate of mortality associated
with childhood diarrhea in developing countries. Unfortu-
nately, although zinc deciency is associated with increased
risk of rotavirus gastroenteritis (178), it does not greatly
increase the development of humoral immunity followed
by vaccination (rotarix), as dened by seroconversion rate
(179). Nonetheless, a pooled analysis of randomized trials
performed in 2000, demonstrated that zinc supplementation
shortens the length of diarrheal episodes and reduced the rate
of treatment failure or death by 42% in zinc-decient children
(180).
Comparable studies of supplementation with zinc before
vaccination have produced similar disappointing results.
Zinc supplementation did not improve seroconversion fol-
lowing administration of the oral poliovirus vaccine in
infants (181), nor did it improve the immunological response
to HBV (182) or inuenza vaccination (183) in the elderly.
Although there remains little evidence that zinc improves
viral vaccination responses, a small number of studies suggest
that zinc may improve antibody titers and antibacterial re-
sponses to pneumococcus (184)andcholerainfections(185).
Conclusions and Future Perspectives
The tight regulation of zinc homeostasis both systemically
and intracellularly indicates that zinc plays an essential
role in human health. Although zinc is a component of
10%ofthehumanproteome,zincindierentforms(free
compared with protein-bound) can stimulate a variety of
signaling events, including the antiviral response. In vitro
studies suggest that free zinc may possess potent antiviral
eects, and are supported by trials of creams, lozenges,
and supplements with high free zinc content. Moreover,
zinc-binding proteins such as the metallothioneins may
possess antiviral roles, although their specic function
remains uncertain. Nonetheless, zinc treatment applied at a
therapeutic dose and in the right form has the potential to
drastically improve the clearance of both chronic and acute
viral infections, as well as their accompanying pathologies
and symptoms. Consequently, the role of zinc as an antiviral
can be separated into 2 categories: 1) zinc supplementation
implemented to improve the antiviral response and systemic
immunity in patients with zinc deciency, and 2)zinc
treatment performed to specically inhibit viral replication
or infection-related symptoms (75,78–82,83,85–91,95–101,
103,104).
Acknowledgments
The authors’ responsibilities were as follows—SR and GA de-
signed the review, all authors performed the study selection,
all authors read and approved the nal paper.
10 Read et al.
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
References
1. Prasad AS, Miale A, Jr., Farid Z, Sandstead HH, Schulert AR. Zinc
metabolism in patients with the syndrome of iron deciency anemia,
hepatosplenomegaly, dwarsm, and hypogonadism. J Lab Clin Med
1963;61:537–49.
2. Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X,
TaipaleJ,HughesTR,WeirauchMT.Thehumantranscriptionfactors.
Cell 2018;172(4):650–65.
3. Andreini C, Bertini I. A bioinformatics view of zinc enzymes. J Inorg
Biochem 2012;111:150–6.
4. Overbeck S, Rink L, Haase H. Modulating the immune response by
oral zinc supplementation: a single approach for multiple diseases.
Arch Immunol Ther Exp (Warsz) 2008;56(1):15–30.
5. Wessells KR, Brown KH. Estimating the global prevalence of zinc
deciency: results based on zinc availability in national food supplies
and the prevalence of stunting. PLoS One 2012;7(11):e50568.
6. KumssaDB,JoyEJ,AnderEL,WattsMJ,YoungSD,WalkerS,Broadley
MR. Dietary calcium and zinc deciency risks are decreasing but
remain prevalent. Sci Rep 2015;5:10974.
7. Himoto T, Masaki T. Associations between zinc deciency and
metabolic abnormalities in patients with chronic liver disease.
Nutrients 2018;10(1). doi: ARTN 88 10.3390/nu10010088.
8. Siva S, Rubin DT, Gulotta G, Wroblewski K, Pekow J. Zinc deciency is
associated with poor clinical outcomes in patients with inammatory
bowel disease. Inamm Bowel Dis 2017;23(1):152–7.
9. Shankar AH, Prasad AS. Zinc and immune function: the
biological basis of altered resistance to infection. Am J Clin Nutr
1998;68(2):447s–63s.
10. Bozym RA, Thompson RB, Stoddard AK, Fierke CA. Measuring
picomolar intracellular exchangeable zinc in PC-12 cells using a
ratiometric uorescence biosensor. ACS Chem Biol 2006;1(2):103–11.
11. Malavolta M, Costarelli L, Giacconi R, Muti E, Bernardini G, Tesei
S, Cipriano C, Mocchegiani E. Single and three-color ow cytometry
assay for intracellular zinc ion availability in human lymphocytes
with Zinpyr-1 and double immunouorescence: relationship with
metallothioneins. Cytometry A 2006;69a(10):1043–53.
12. Vinkenborg JL, Nicolson TJ, Bellomo EA, Koay MS, Rutter GA, Merkx
M. Genetically encoded FRET sensors to monitor intracellular Zn2+
homeostasis. Nat Methods 2009;6(10):737–40.
13. Kambe T, Tsuji T, Hashimoto A, Itsumura N. The physiological,
biochemical, and molecular roles of zinc transporters in zinc
homeostasis and metabolism. Physiol Rev 2015;95(3):749–84.
14. Duncan A, Yacoubian C, Watson N, Morrison I. The risk of copper
deciency in patients prescribed zinc supplements. J Clin Pathol
2015;68(9):723–5.
15. Becker KW, Skaar EP. Metal limitation and toxicity at the interface
between host and pathogen. FEMS MicrobiolRe v 2014;38(6):1235–49.
16.BotellaH,PeyronP,LevillainF,PoinclouxR,PoquetY,BrandliI,
Wang C, Tailleux L, Tilleul S, Charriere GM, et al. Mycobacterial
p(1)-type ATPases mediate resistance to zinc poisoning in human
macrophages. Cell Host Microbe 2011;10(3):248–59.
17. Chen CC, Huang JL, Chang CJ, Kong MS. Fecal calprotectin as
a correlative marker in clinical severity of infectious diarrhea and
usefulness in evaluating bacterial or viral pathogens in children. J
Pediatr Gastroenterol Nutr 2012;55(5):541–7.
18. Lazarczyk M, Favre M. Role of Zn2+ions in host-virus interactions. J
Virol 2008;82(23):11486–94.
19.LazarczykM,PonsC,MendozaJA,CassonnetP,JacobY,FavreM.
Regulation of cellular zinc balance as a potential mechanism of EVER-
mediated protection against pathogenesis by cutaneous oncogenic
human papillomaviruses. J Exp Med 2008;205(1):35–42.
20. Kim YM, Reed W, Wu W, Bromberg PA, Graves LM, Samet JM. Zn2+-
induced IL-8 expression involves AP-1, JNK, and ERK activities in
human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol
2006;290(5):L1028–35.
21. Bravo IG, Alonso A. Mucosal human papillomaviruses encode four
dierent E5 proteins whose chemistry and phylogeny correlate with
malignant or benign growth. J Virol 2004;78(24):13613–26.
22. Schiman M, Herrero R, Desalle R, Hildesheim A, Wacholder S,
Rodriguez AC, Bratti MC, Sherman ME, Morales J, Guillen D, et al.
The carcinogenicity of human papillomavirus types reects viral
evolution. Virology 2005;337(1):76–84.
23. Subramanian Vignesh K, Deepe GS, Jr. Metallothioneins: emerging
modulators in immunity and infection. Int J Mol Sci 2017;18(10). doi:
10.3390/ijms18102197.
24. Babula P, Masarik M, Adam V, Eckschlager T, Stiborova M,
TrnkovaL,SkutkovaH,ProvaznikI,HubalekJ,KizekR.
Mammalian metallothioneins: properties and functions. Metallomics
2012;4(8):739–50.
25. Hennigar SR, Kelley AM, McClung JP. Metallothionein and zinc
transporter expression in circulating human blood cells as biomarkers
of zinc status: a systematic review. Adv Nutr 2016;7(4):735–46.
26. Grzywacz A, Gdula-Argasinska J, Muszynska B, Tyszka-Czochara M,
LibrowskiT, Opoka W. Metal responsive transcriptionfactor 1 (MTF-
1) regulates zinc dependent cellular processes at the molecular level.
Acta Biochim Pol 2015;62(3):491–8.
27. Friedman RL, Manly SP, McMahon M, Kerr IM, Stark GR.
Transcriptional and posttranscriptional regulation of interferon-
induced gene expression in human cells. Cell 1984;38(3):745–55.
28. Read SA, O’Connor KS, Suppiah V, Ahlenstiel CLE, Obeid S, Cook
KM,CunninghamA,DouglasMW,HoggPJ,BoothD,etal.Zinc
is a potent and specic inhibitor of IFN-λ3 signalling. Nat Commun
2017;8:15245.
29. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler
AM, Haussler D. The human genome browser at UCSC. Genome Res
2002;12(6):996–1006.
30. Li K, Prow T, Lemon SM, Beard MR. Cellular response to conditional
expression of hepatitis C virus core protein in Huh7 cultured human
hepatoma cells. Hepatology 2002;35(5):1237–46.
31. Zilliox MJ, Parmigiani G, Grin DE. Gene expression patterns in
dendritic cells infected with measles virus compared with other
pathogens. Proc Natl Acad Sci U S A 2006;103(9):3363–8.
32. Mindaye ST, Ilyushina NA, Fantoni G, Alterman MA, Donnelly
RP, Eichelberger MC. Impact of inuenza A virus infection on the
proteomes of human bronchoepithelial cells from dierent donors. J
Proteome Res 2017;16(9):3287–97.
33. Raymond AD, Gekonge B, Giri MS, Hancock A, Papasavvas E,
Chehimi J, Kossenkov AV, Nicols C, Yousef M, Mounzer K, et al.
Increased metallothionein gene expression, zinc, and zinc-dependent
resistance to apoptosis in circulating monocytes during HIV viremia.
J Leukoc Biol 2010;88(3):589–96.
34. ReadSA,ParnellG,BoothD,DouglasMW,GeorgeJ,AhlenstielG.
The antiviral role of zinc and metallothioneins in hepatitis C infection.
J Viral Hepat 2018;25(5):491–501.
35. Ilback NG, Glynn AW, Wikberg L, Netzel E, Lindh U. Metallothionein
isinducedandtraceelementbalancechangedintargetorgansofa
common viral infection. Toxicology 2004;199(2–3):241–50.
36. Perry DK, Smyth MJ, Stennicke HR, Salvesen GS, Duriez P, Poirier
GG, Hannun YA. Zinc is a potent inhibitor of the apoptotic protease,
caspase-3—a novel target for zinc in the inhibition of apoptosis. J Biol
Chem 1997;272(30):18530–3.
37. Shimoda R, Achanzar WE, Qu W, Nagamine T, Takagi H, Mori
M, Waalkes MP. Metallothionein is a potential negative regulator of
apoptosis. Toxicol Sci 2003;73(2):294–300.
38. Kanekiyo M, Itoh N, Mano M, Kawasaki A, Tanaka J, Muto N, Tanaka
K. Cellular zinc status regulates cytomegalovirus major immediate-
early promoter. Antiviral Res 2000;47(3):207–14.
39. Kanekiyo M, Itoh N, Kawasaki A, Tanaka J, Nakanishi T, Tanaka
K. Zinc-induced activation of the human cytomegalovirus major
immediate-early promoter ismediated by metallothionein and nuclear
factor-κB. Toxicol Appl Pharmacol 2001;173(3):146–53.
40. Zhao J, He SP, Minassian A, Li JH, Feng PH. Recent advances on
viral manipulation of NF-κB signaling pathway. Curr Opin Virol
2015;15:103–11.
41.QiuM,ChenY,ChuY,SongS,YangN,GaoJ,WuZ.Zinc
ionophores pyrithione inhibits herpes simplex virus replication
Zinc as an antiviral 11
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
through interfering with proteasome function and NF-κBactivation.
Antiviral Res 2013;100(1):44–53.
42. Zhou Z, Wang L, Song Z, Saari JT, McClain CJ, Kang YJ. Abrogation
of nuclear factor-κB activation is involved in zinc inhibition of
lipopolysaccharide-induced tumor necrosis factor-αproduction and
liver injury. Am J Pathol 2004;164(5):1547–56.
43. Prasad AS, Bao B, Beck FWJ, Sarkar FH. Zinc-suppressed
inammatory cytokines by induction of A20-mediated inhibition of
nuclear factor-κB. Nutrition 2011;27(7–8):816–23.
44. Kim CH, Kim JH, Lee J, Ahn YS. Zinc-induced NF-κBinhibitioncan
be modulated by changes in the intracellular metallothionein level.
Toxicol Appl Pharmacol 2003;190(2):189–96.
45. Tellinghuisen TL, Marcotrigiano J, Gorbalenya AE, Rice CM. The
NS5A protein of hepatitis C virus is a zinc metalloprotein. J Biol Chem
2004;279(47):48576–87.
46. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P,
Rice CM. A diverse range of gene products are eectors of the type I
interferon antiviral response. Nature 2011;472(7344):481–5.
47. Rukgauer M, Klein J, Kruse-Jarres JD. Reference values for the
trace elements copper, manganese, selenium, and zinc in the
serum/plasma of children, adolescents, and adults. J Trace Elem Med
Biol 1997;11(2):92–8.
48. KumelG,SchraderS,ZentgrafH,DausH,BrendelM.Themechanism
of the antiherpetic activity of zinc-sulfate. J Gen Virol 1990;71:
2989–97.
49. Krezel A, Maret W. Zinc-buering capacity of a eukaryotic cell at
physiological pZn. J Biol Inorg Chem 2006;11(8):1049–62.
50. Colvin RA, Bush AI, Volitakis I, Fontaine CP, Thomas D, Kikuchi
K, Holmes WR. Insights into Zn2+homeostasis in neurons from
experimental and modeling studies. Am J Physiol Cell Physiol
2008;294(3):C726–C42.
51. Eby GA. Zinc ion availability—the determinant of ecacy in zinc
lozenge treatment of common colds. J Antimicrob Chemother
1997;40(4):483–93.
52. Fridlender B, Chejanovsky N, Becker Y. Selective inhibition of
herpes simplex virus type 1 DNA polymerase by zinc ions. Virology
1978;84(2):551–4.
53. Gupta P, Rapp F. Eect of zinc ions on synthesis of herpes
simplex virus type 2-induced polypeptides. Proc Soc Exp Biol Med
1976;152(3):455–8.
54. Arens M, Travis S. Zinc salts inactivate clinical isolates of herpes
simplex virus in vitro. J Clin Microbiol 2000;38(5):1758–62.
55. Bourne N, Stegall R, Montano R, Meador M, Stanberry LR, Milligan
GN. Ecacy and toxicity of zinc salts as candidate topical microbicides
against vaginal herpes simplex virus type 2 infection. Antimicrob
Agents Chemother 2005;49(3):1181–3.
56. Kenney J, Rodriguez A, Kizima L, Seidor S, Menon R, Jean-Pierre
N, Pugach P, Levendosky K, Derby N, Gettie A, et al. A modied
zinc acetate gel, a potential nonantiretroviral microbicide, is safe and
eective against simian-human immunodeciency virus and herpes
simplex virus 2 infection in vivo. Antimicrob Agents Chemother
2013;57(8):4001–9.
57. Godfrey HR, Godfrey NJ, Godfrey JC, Riley D. A randomized clinical
trial on the treatment of oral herpes with topical zinc oxide/glycine.
Altern Ther Health Med 2001;7(3):49–56.
58. Mahajan BB, Dhawan M, Singh R. Herpes genitalis—topical zinc
sulfate: an alternative therapeutic and modality. Indian J Sex Transm
Dis AIDS 2013;34(1):32–4.
59. Shishkov S, Varadinova T, Bontchev P, Nachev C, Michailova E.
Complexes of zinc with picolinic and aspartic acids inactivate free
varicella-zoster virions. Met Based Drugs 1996;3(1):11–4.
60. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ,
van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA
polymerase activity in vitro and zinc ionophores block the replication
of these viruses in cell culture. PLoS Pathog 2010;6(11):e1001176.
61. Butterworth BE, Korant BD. Characterization of the large picornaviral
polypeptides produced in the presence of zinc ion. J Virol
1974;14(2):282–91.
62. Nakai K, Lucas-Lenard J. Processing of mengovirus precursor
polypeptides in the presence of zinc ions and sulydryl compounds. J
Virol 1976;18(3):918–25.
63. Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld
FJM, Seipelt J. Antiviral activity of the zinc ionophores pyrithione
and hinokitiol against picornavirus infections. J Virol 2009;83(1):
58–64.
64. Polatnick J, Bachrach HL. Eect of zinc and other chemical agents
on foot-and-mouth-disease virus replication. Antimicrob Agents
Chemother 1978;13(5):731–4.
65. Firpo EJ, Palma EL. Inhibition of foot and mouth disease virus and
procapsid synthesis by zinc ions. Brief report. Arch Virol 1979;61(1–
2):175–81.
66. Ferrari E, Wright-Minogue J, Fang JW, Baroudy BM, Lau JY, Hong
Z. Characterization of soluble hepatitis C virus RNA-dependent
RNA polymerase expressed in Escherichia coli. J Virol 1999;73(2):
1649–54.
67. YuasaK,NaganumaA,SatoK,IkedaM,KatoN,TakagiH,MoriM.
Zinc is a negative regulator of hepatitis C virus RNA replication. Liver
Int 2006;26(9):1111–8.
68. Zhang ZY, Reardon IM, Hui JO, Oconnell KL, Poorman RA,
Tomasselli AG, Heinrikson RL. Zinc inhibition of renin and the
protease from human immunodeciency virus type 1. Biochemistry
(Mosc) 1991;30(36):8717–21.
69. HaraguchiY,SakuraiH,HussainS,AnnerBM,HoshinoH.Inhibition
of HIV-1 infection by zinc group metal compounds. Antiviral Res
1999;43(2):123–33.
70. Fenstermacher KJ, DeStefano JJ. Mechanism of HIV reverse
transcriptase inhibition by zinc formation of a highly stable enzyme-
(primer-template) complex with profoundly diminished catalytic
activity. J Biol Chem 2011;286(47):40433–42.
71. Bae SN, Lee KH, Kim JH, Lee SJ, Park LO. Zinc induces apoptosis on
cervical carcinoma cells by p53-dependent and -independent pathway.
Biochem Biophys Res Commun 2017;484(1):218–23.
72. Suara RO, Crowe JE , Jr.E ect of zinc salts on respiratory sy ncytial virus
replication. Antimicrob Agents Chemother 2004;48(3):783–90.
73. Korant BD, Kauer JC, Butterworth BE. Zinc ions inhibit replication of
rhinoviruses. Nature 1974;248(5449):588–90.
74. Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein
cleavage: interaction of zinc with capsid polypeptides. J Virol
1976;18(1):298–306.
75. Hung M, Gibbs CS, Tsiang M. Biochemical characterization
of rhinovirus RNA-dependent RNA polymerase. Antiviral Res
2002;56(2):99–114.
76. Corver J, Bron R, Snippe H, Kraaijeveld C, Wilschut J. Membrane
fusion activity of Semliki Forest virus in a liposomal model system:
specic inhibition by Zn2+ions. Virology 1997;238(1):14–21.
77. Liu CY, Kielian M. Identication of a specic region in the E1 fusion
protein involved in zinc inhibition of Semliki Forest virus fusion. J
Virol 2012;86(7):3588–94.
78. Bracha M, Schlesinger MJ. Inhibition of Sindbis virus-replication by
zinc ions. Virology 1976;72(1):272–7.
79. Wei ZY, Burwinkel M, Palissa C, Ephraim E, Schmidt MFG. Antiviral
activity of zinc salts against transmissible gastroenteritis virus in vitro.
Vet Microbiol 2012;160(3–4):468–72.
80. Zaslavsky V. Inhibition of vaccinia virus growth by zinc ions—eect
on early RNA and thymidine kinase synthesis. J Virol 1979;29(1):405–
8.
81. Katz E, Margalith E. Inhibition of vaccinia virus maturation by zinc-
chloride. Antimicrob Agents Chemother 1981;19(2):213–7.
82. Shuman S, Golder M, Moss B. Characterization of vaccinia virus-
DNA topoisomerase-I expressed in Escherichia c oli.JBiolChem
1988;263(31):16401–7.
83. Iovino L, Mazziotta F, Carulli G, Guerrini F, Morganti R, Mazzotti V,
MaggiF,MaceraL,OrciuoloE,BudaG,etal.High-dosezincoral
supplementation after stem cell transplantation causes an increase of
TRECs and CD4+naïve lymphocytes and prevents TTV reactivation.
Leuk Res 2018;70:20–4.
12 Read et al.
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
84. Iraji F, Faghihi G. A randomized double-blind placebo-controlled
clinical trial of two strengths of topical zinc sulfate solution against
recurrent herpes simplex. Arch Iranian Med 2002;6(1):13–5.
85. Turner RB, Cetnarowski WE. Eect of treatment with zinc gluconate
or zinc acetate on experimental and natural colds. Clin Infect Dis
2000;31(5):1202–8.
86. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common
colds by zinc gluconate lozenges in a double-blind study. Antimicrob
Agents Chemother 1984;25(1):20–4.
87. Godfrey JC, Sloane BC, Smith DS, Turco JH, Mercer N, Godfrey NJ.
Zinc gluconate and the common cold—a controlled clinical-study. J
Int Med Res 1992;20(3):234–46.
88. Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate
lozenges for treating the common cold—a randomized, double-blind,
placebo-controlled study. Ann Intern Med 1996;125(2):81–8. doi:
10.7326/0003-4819-125-2-199607150-00001.
89. Petrus EJ, Lawson KA, Bucci LR, Blum K. Randomized, double-
masked, placebo-controlled clinical study of the eectiveness of zinc
acetate lozenges on common cold symptoms in allergy-tested subjects.
Curr Ther Res 1998;59(9):595–607.
90. Prasad AS, Fitzgerald JT, Bao B, Beck FWJ, Chandrasekar PH.
Duration of symptoms and plasma cytokine levels in patients with the
common cold treated with zinc acetate—a randomized, double-blind,
placebo-controlled trial. Ann Intern Med 2000;133(4):245–52.
91. Prasad AS, Beck FWJ, Bao B, Snell D, Fitzgerald JT. Duration and
severity of symptoms and levels of plasma interleukin-1 receptor
antagonist, soluble tumor necrosis factor receptor, and adhesion
molecules in patients with common cold treated with zinc acetate. J
Infect Dis 2008;197(6):795–802.
92. Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in the
treatment of recalcitrant viral warts: randomized placebo-controlled
clinical trial. Br J Dermatol 2002;146(3):423–31.
93. Sharquie KE, Khorsheed AA, Al-Nuaimy AA. Topical zinc sulphate
solution for treatment of viral warts. Saudi Med J 2007;28(9):1418–21.
94. Yagboobi R, Sadighha A, Baktash D. Evaluation of oral zinc sulfate
eect on recalcitrant multiple viral warts: a randomized placebo-
controlled clinical trial. J Am Acad Dermatol 2009;60(4):706–8.
95. Lopez-Garcia DR, Gomez-Flores M, Arce-Mendoza AY, de la
Fuente-Garcia A, Ocampo-Candiani J. Oral zinc sulfate for
unresponsive cutaneous viral warts: too good to be true? A double-
blind, randomized, placebo-controlled trial. Clin Exp Dermatol
2009;34(8):E984–E5.
96. Mohamed EEM, Tawk KM, Mahmoud AM. The clinical eectiveness
of intralesional injection of 2% zinc sulfate solution in the
treatment of common warts. Scientica 2016 ;2016:1082979. doi:
10.1155/2016/1082979.
97. Al-Waiz MM, Al-Nuaimy AA, Aljobori HA, Abdulameer MJ.
Lary ngeal papillomatosis tre ated by oral zinc sulphate. Ann Saudi Med
2006;26(5):411–3.
98. Mocchegiani E, Veccia S, Ancarani F, Scalise G, Fabris N. Benet of
oral zinc supplementation as an adjunct to zidovudine (Azt) therapy
against opportunistic infections in AIDS. Int J Immunopharmacol
1995;17(9):719–27.
99. Zazzo JF, Rouveix B, Rajagopalon P, Levacher M, Girard PM. Eect
of zinc on the immune status of zinc-depleted AIDS related complex
patients. Clin Nutr 1989;8(5):259–61.
100. Bobat R, Coovadia H, Stephen C, Naidoo KL, McKerrow N, Black RE,
Moss W. Safety and ecacy of zinc supplementation for children with
HIV-1 infection in South Africa: a randomised double-blind placebo-
controlled trial. Lancet 2005;366(9500):1862–7.
101. Villamor E, Aboud S, Koulinska IN, Kupka R, Urassa W, Chaplin B,
Msamanga G, Fawzi WW. Zinc supplementation to HIV-1-infected
pregnant women: eects on maternal anthropometry, viral load, and
early mother-to-child transmission. Eur J Clin Nutr 2006;60(7):862–9.
102. TakagiH, Nagamine T, Abe T, Takayama H, Sato K, Otsuka T, Kakizaki
S, Hashimoto Y, Matsumoto T, Kojima A, et al. Zinc supplementation
enhances the response to interferon therapy in patients with chronic
hepatitis C. J Viral Hepat 2001;8(5):367–71.
103. Ko WS, Guo CH, Hsu GS, Chiou YL, Yeh MS, Yaun SR. The eect of
zinc supplementation on the treatment of chronic hepatitis C patients
with interferon and ribavirin. Clin Biochem 2005;38(7):614–20.
104. Himoto T, Hosomi N, Nakai S, Deguchi A, Kinekawa F, Matsuki M,
YachidaM,MasakiT,KurokochiK,WatanabeS,etal.Ecacyofzinc
administration in patients with hepatitis C virus-related chronic liver
disease. Scand J Gastroenterol 2007;42(9):1078–87.
105. Matsumura H, Nirei K, Nakamura H, Arakawa Y, Higuchi T, Hayashi
J, Yamagami H, Matsuoka S, Ogawa M, Nakajima N, et al. Zinc
supplementation therapy improves the outcome of patients with
chronic hepatitis C. J Clin Biochem Nutr 2012;51(3):178–84.
106. Murakami Y, Koyabu T, Kawashima A, Kakibuchi N, Kawakami
T, Takaguchi K, Kita K, Okita M. Zinc supplementation prevents
the increase of transaminase in chronic hepatitis C patients during
combination therapywith peg ylated interferon alpha-2b and ribavirin.
J Nutr Sci Vitaminol (Tokyo) 2007;53(3):213–8.
107. Lanke K, Krenn BM, Melchers WJ, Seipelt J, van Kuppeveld FJ. PDTC
inhibits picornavirus polyprotein processing and RNA replication by
transporting zinc ions into cells. J Gen Virol 2007;88(Pt 4):1206–17.
108. Eby GA. Zinc lozenges as cure for the common cold—a review and
hypothesis. Med Hypotheses 2010;74(3):482–92.
109. Hemila H. Zinc lozenges may shorten the duration of colds: a
systematic review. Open Respir Med J 2011;5:51–8.
110. Uchide N, Ohyama K, Bessho T, Yuan B, Yamakawa T. Eect
of antioxidants on apoptosis induced by inuenza virus infection:
inhibition of viral gene replication and transcription with pyrrolidine
dithiocarbamate. Antiviral Res 2002;56(3):207–17.
111. Oxford JS, Perrin DD. Inhibition of the particle-associated RNA-
dependent RNA polymerase activity of inuenza viruses by chelating
agents. J Gen Virol 1974;23(1):59–71.
112. Alter MJ. The epidemiology of acute and chronichepatitis C. Clin Liver
Dis 1997;1(3):559–68, vi–vii.
113. Nagamine T, Takagi H, Hashimoto Y, Takayama H, Shimoda R,
Nomura N, Suzuki K, Mori M, Nakajima K. The possible role of zinc
and metallothionein in the liver on the therapeutic eect of IFN-αto
hepatitis C patients. Biol Trace Elem Res 1997;58(1–2):65–76.
114. Garo H, WilschutJ, Liljestrom P, Wahlberg JM, Bron R, Suomalainen
M,SmythJ,SalminenA,BarthBU,ZhaoH,etal.Assemblyandentry
mechanisms of Semliki Forest virus. Arch Virol Suppl 1994;9:329–38.
115. Zaitseva E, Mittal A, Grin DE, Chernomordik LV. Class II fusion
protein of alphaviruses drives membrane fusion through the same
pathway as class I proteins. J Cell Biol 2005;169(1):167–77.
116. Wellenreuther G, Cianci M, Tucoulou R, Meyer-Klaucke W, Haase H.
The ligand environment of zinc stored in vesicles. Biochem Biophys
Res Commun 2009;380(1):198–203.
117. Klemm V, Mitchell J, Cortez-Jugo C, Cavalieri F, Symonds G, Caruso
F, Kelleher AD, Ahlenstiel C. Achieving HIV-1 control through RNA-
directed gene regulation. Genes-Basel 2016;7(12). doi: ARTN 119
10.3390/genes7120119.
118. Levinson W, Faras A, Woodson B, Jackson J, Bishop JM. Inhibition
of RNA-dependent DNA polymerase of Rous sarcoma virus by
thiosemicarbazones and several cations. Proc Natl Acad Sci U S A
1973;70(1):164–8.
119. Palan PR, Eidino ML. Specic eect of zinc ions on DNA-
polymerase activity of avian myeloblastosis virus. Mol Cell Biochem
1978;21(2):67–9.
120. York DM, Darden TA, Pedersen LG, Anderson MW. Molecular
modeling studies suggest that zinc ions inhibit HIV-1 protease
by binding at catalytic aspartates. Environ Health Perspect
1993;101(3):246–50.
121. Xu YN, Zhu HY, Wilcox CK, van’t Wout A, Andrus T, Llewellyn
N, Stamatatos L, Mullins JI, Corey L, Zhu TF. Blood monocytes
harbor HIV type 1 strains with diversied phenotypes including
macrophage-specic CCR5 virus. J Infect Dis 2008;197(2):
309–18.
122. Swingler S, Mann AM, Zhou J, Swingler C, Stevenson M. Apoptotic
killing of HIV-1-infected macrophages is subverted by the viral
envelope glycoprotein. PLoS Pathog 2007;3(9):1281–90.
Zinc as an antiviral 13
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
123. Poudel KC, Bertone-Johnson ER, Poudel-Tandukar K. Serum zinc
concentration and C-reactive protein in individuals with human
immunodeciency virus infection: the POsitive Living with HIV
(POLH) study. Biol Trace Elem Res 2016;171(1):63–70.
124. Baum MK, Lai SH, Sales S, Page JB, Campa A. Randomized, controlled
clinical trial of zinc supplementation to prevent immunological failure
in HIV-infected adults. Clin Infect Dis 2010;50(12):1653–60.
125. Baum MK, Campa A, Lai SG, Lai H, Page JB. Zinc status in human
immunodeciency virus type 1 infection and illicit drug use. Clin
Infect Dis 2003;37:S117–S23.
126. Visser ME, Durao S, Sinclair D, Irlam JH, Siegfried N. Micronutrient
supplementation in adults with HIV infection. Cochrane
Database Syst Rev 2017;(5):CD003650. doi: ARTN CD003650
10.1002/14651858.CD003650.pub4.
127. Kenney J, Aravantinou M, Singer R, Hsu M, Rodriguez A, Kizima
L, Abraham CJ, Menon R, Seidor S, Chudolij A, et al. An
antiretroviral/zinc combination gel provides 24 hours of complete
protection against vaginal SHIV infection in macaques. PLoS One
2011;6(1):e15835. doi: ARTN e15835 10.1371/journal.pone.0015835.
128. Mizenina O, Hsu M, Jean-Pierre N, Aravantinou M, Levendosky K,
Paglini G, Zydowsky TM, Robbiani M, Fernandez-Romero JA. MIV-
150 and zinc acetate combination provides potent and broad activity
against HIV-1. Drug Deliv Transl Re 2017;7(6):859–66.
129. de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of
cancer attributable to HPV by site, country and HPV type. Int J Cancer
2017;141(4):664–70.
130. Hoppe-Seyler K, Bossler F, Braun JA, Herrmann AL, Hoppe-Seyler F.
The HPV E6/E7 oncogenes: key factors for viral carcinogenesis and
therapeutic targets. Trends Microbiol 2018;26(2):158–68.
131. Simonart T, de Maertelaer V. Systemic treatments for cutaneous warts:
a systematic review. J Dermatol Treat 2012;23(1):72–7.
132. Raza N, Khan DA. Zinc deciency in patients with persistent viral
warts. J Coll Physicians Surg Pak 2010;20(2):83–6.
133. Kim JH, Bae SN, Lee CW, Song MJ, Lee SJ, Yoon JH, Lee KH, Hur
SY,ParkTC,ParkJS.Apilotstudytoinvestigatethetreatmentof
cervical human papillomavirus infection with zinc-citrate compound
(CIZAR®). Gynecol Oncol 2011;122(2):303–6.
134. Kizima L, Rodriguez A, Kenney J, Derby N, Mizenina O, Menon
R, Seidor S, Zhang SM, Levendosky K, Jean-Pierre N, et al.
A potent combination microbicide that targets SHIV-RT, HSV-
2 and HPV. PLoS One 2014;9(4):e94547. doi: ARTN e94547
10.1371/journal.pone.0094547.
135. Maywald M, Wessels I, Rink L. Zinc signals and immunity. Int J Mol
Sci 2017;18(10). doi: ARTN 2222 10.3390/ijms18102222.
136. Pandey S, Kawai T, Akira S. Microbial sensing by toll-like receptors
and intracellular nucleic acid sensors. Cold Spring Harb Perspect Biol
2015;7(1):a016246. doi: ARTN a016246 10.1101/cshperspect.a016246.
137. Lazear HM, Nice TJ, Diamond MS. Interferon-λ: immune functions
at barrier surfaces and beyond. Immunity 2015;43(1):15–28.
138. Brieger A, Rink L, Haase H. Dierential regulation of TLR-dependent
MyD88 and TRIF signaling pathways by free zinc ions. J Immunol
2013;191(4):1808–17.
139. Liu MJ, Bao SY, Galvez-Peralta M, Pyle CJ, Rudawsky AC, Pavlovicz
RE, Killilea DW, Li CL, Nebert DW, Wewers MD, et al. ZIP8 regulates
host defense through zinc-mediated inhibition of NF-κB. Cell Rep
2013;3(2):386–400.
140. Hoshino K, Sugiyama T, Matsumoto M, Tanaka T, Saito M, Hemmi
H, Ohara O, Akira S, Kaisho T. IκB kinase-αis critical for
interferon-αproduction induced by toll-like receptors 7 and 9. Nature
2006;440(7086):949–53.
141. Han KJ, Su XQ, Xu LG, Bin LH, Zhang J, Shu HB. Mechanisms of
the TRIF-induced interferon-stimulated response element and NF-κB
activation and apoptosis pathways. J Biol Chem 2004;279(15):15652–
61.
142. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E,
Golenbock DT, Coyle AJ, Liao SM, Maniatis T. IKKεand TBK1
are essential components of the IRF3 signaling pathway. Nat Immunol
2003;4(5):491–6.
143. Shembade N, Ma A, Harhaj EW. Inhibition of NF-κBsignaling
by A20 through disruption of ubiquitin enzyme complexes. Science
2010;327(5969):1135–9.
144. Wang YY, Li LY, Han KJ, Zhai ZH, Shu HB. A20 is a potent inhibitor
of TLR3-and Sendai virus-induced activation of NF-κB and ISRE and
IFN-βpromoter. FEBS Lett 2004;576(1–2):86–90.
145. Lin RT, Yang L, Nakhaei P, Sun Q, Sharif-Askari E, Julkunen I,
Hiscott J. Negative regulation of the retinoic acid-inducible gene I-
induced antiviral state by the ubiquitin-editing protein A20. J Biol
Chem 2006;281(4):2095–103.
146. Maelfait J, Roose K, Bogaert P, Sze M, Saelens X, Pasparakis
M, Carpentier I, van Loo G, Beyaert R. A20 (Tnfaip3)
deciency in myeloid cells protects against inuenza A virus
infection. PLoS Pathog 2012;8(3):e1002570. doi: ARTN e1002570
10.1371/journal.ppat.1002570.
147. Yabe-Wada T, Matsuba S, Takeda K, Sato T, Suyama M, Ohkawa
Y, Takai T, Shi HF, Philpott CC, Nakamura A. TLR signals
posttranscriptionally regulate the cytokine tracking mediator
sortilin. Sci Rep 2016;6: 26566. doi: ARTN 26566 10.1038/srep26566.
148. Mortensen MB, Kjolby M, Gunnersen S, Larsen JV, Palmfeldt J,
Falk E, Nykjaer A, Bentzon JF. Targeting sortilin in immune cells
reduces proinammatory cytokines and atherosclerosis. J Clin Invest
2014;124(12):5317–22.
149. Radhakrishnan R, Walter LJ, Hruza A, Reichert P, Trotta PP,
Nagabhushan TL, Walter MR. Zinc mediated dimer of human
interferon-α2b revealed by X-ray crystallography. Structure
1996;4(12):1453–63.
150. Berg K, Bolt G, Andersen H, Owen TC. Zinc potentiates the
antiviral action of human IFN-αtenfold. J Interferon Cytokine Res
2001;21(7):471–4.
151. O’Connor KS, Parnell G, Patrick E, Ahlenstiel G, Suppiah V, van
der Poorten D, Read SA, Leung R, Douglas MW, Yang JY, et al.
Hepatic metallothionein expression in chronic hepatitis C virus
infection is IFNL3 genotype-dependent. Genes Immun 2014;15(2):
88–94.
152. Brautigan DL, Bornstein P, Gallis B. Phosphotyrosyl-protein
phosphatase—specic inhibition by Zn-2+.JBiolChem
1981;256(13):6519–22.
153. Shanker V, Trincucci G, Heim HM, Duong HT. Protein phosphatase
2A impairs IFNα-induced antiviral activity against the hepatitis C
virus through the inhibition of STAT1 tyrosine phosphorylation. J
Viral Hepat 2013;20(9):612–21.
154. You M, Yu DH, Feng GS. Shp-2 tyrosine phosphatase functions as a
negative regulator of the interferon-stimulated Jak/STATp athway. Mol
Cell Biol 1999;19(3):2416–24.
155. David M, Chen HYE, Goelz S, Larner AC, Neel BG. Dierential
regulation of the α/βinterferon-stimulated Jak/STAT pathway by the
SH2 domain-containing tyrosine phosphatase SHPTP1. Mol Cell Biol
1995;15(12):7050–8.
156. Xiong Y, Luo DJ, Wang XL, Qiu M, Yang Y, Yan X, Wang JZ, Ye QF,
Liu R. Zinc binds to and directly inhibits protein phosphatase 2A in
vitro. Neurosci Bull 2015;31(3):331–7.
157. Haase H, Maret W. Intracellular zinc uctuations modulate protein
tyrosine phosphatase activity in insulin/insulin-like growth factor-1
signaling. Exp Cell Res 2003;291(2):289–98.
158. Haase H, Maret W. Fluctuations of cellular, available zinc modulate
insulin signaling via inhibition of protein tyrosine phosphatases. J
Trace Elem Med Biol 2005;19(1):37–42.
159. Long LY, Deng YZ, Yao F, Guan DX, Feng YY, Jiang H, Li XB, Hu PT,
LuXC,WangH,etal.RecruitmentofphosphatasePP2AbyRACK1
adaptor protein deactivates transcription factor IRF3 and limits type I
interferon signaling. Immunity 2014;40(4):515–29.
160. Li S, Zhu MZ, Pan RG, Fang T, Cao YY, Chen SL, Zhao XL, Lei
CQ, Guo L, Chen Y, et al. The tumor suppressor PTEN has a
critical role in antiviral innate immunity. Nat Immunol 2016;17(3):
241–9.
161. Plum LM, Brieger A, Engelhardt G, Hebel S, Nessel A, Arlt M,
Kaltenberg J, Schwaneberg U, Huber M, Rink L, et al. PTEN-inhibition
14 Read et al.
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
by zinc ions augments interleukin-2-mediated Akt phosphorylation.
Metallomics 2014;6(7):1277–87.
162. Yoshimura A, Naka T, KuboM. SOCS proteins, cytokine signalling and
immune regulation. Nat Rev Immunol 2007;7(6):454–65.
163. Liuzzi JP, Wong CP, Ho E, Tracey A. Regulation of hepatic suppressor
of cytokine signaling 3 by zinc. J Nutr Biochem 2013;24(6):1028–33.
164. Lonnerdal B. Dietary factors inuencing zinc absorption. J Nutr
2000;130(5):1378s–83s.
165. Hunt JR, Beiseigel JM, Johnson LK. Adaptation in human zinc
absorption as inuenced by dietary zinc and bioavailability. Am J Clin
Nutr 2008;87(5):1336–45.
166. Yasuda H, Tsutsui T. Infants and elderlies are susceptible to zinc
deciency. Sci Rep 2016;6:21850.
167. Cakman I, Kirchner H, Rink L. Zinc supplementation reconstitutes
the production of interferon-αby leukocytes from elderly persons. J
Interferon Cytokine Res 1997;17(8):469–72.
168. Prasad AS, Beck FW, Bao B, Fitzgerald JT, Snell DC, Steinberg JD,
Cardozo LJ. Zinc supplementation decreases incidence of infections
in the elderly : eect of zinc on generation of cytokines and oxidative
stress. Am J Clin Nutr 2007;85(3):837–44.
169. Mills PR, Fell GS, Bessent RG, Nelson LM, Russell RI. A study of zinc
metabolism in alcoholic cirrhosis. Clin Sci 1983;64(5):527–35.
170. Manari AP, Preedy VR, Peters TJ. Nutritional intake of hazardous
drinkers and dependent alcoholics in the UK. Addict Biol
2003;8(2):201–10.
171. Dinsmore W, Callender ME, McMaster D, Todd SJ, Love AHG. Zinc
absorption in alcoholics using Zn-65. Digestion 1985;32(4):238–42.
172. Sun Q, Li Q, Zhong W, Zhang JY, Sun XH, Tan XB, Yin XM, Sun XG,
Zhang X, Zhou ZX. Dysregulation of hepatic zinc transporters in a
mouse model of alcoholic liver disease. Am J Physiol GastrointestLiver
Physiol 2014;307(3):G313–G22.
173. Zhong W, McClain CJ, Cave M, Kang YJ, Zhou ZX. The role of zinc
deciency in alcohol-induced intestinal barrier dysfunction. Am J
Physiol Gastrointest Liver Physiol 2010;298(5):G625–G33.
174. Konig J, Wells J, Cani PD, Garcia-Rodenas CL, MacDonald T,
Mercenier A, Whyte J, Troost F, Brummer RJ. Human intestinal
barrier function in health and disease. Clin Transl Gastroenterol
2016;7(10):e196.
175. Lambert JC, Zhou ZX, Wang LP, Song ZY, McClain CJ, Kang YJ.
Prevention of alterations in intestinal permeability is involved in zinc
inhibition of acute ethanol-induced liver damage in mice. J Pharmacol
Exp Ther 2003;305(3):880–6.
176. Alam AN, Sarker SA, Wahed MA, Khatun M, Rahaman MM. Enteric
protein loss and intestinal permeability changes in children during
acute shigellosis and after recovery—eect of zinc supplementation.
Gut 1994;35(12):1707–11.
177. Asdamongkol N, Phanachet P, Sungkanuparph S. Low plasma zinc
levels and immunological responses to zinc supplementation in HIV-
infected patients with immunological discordance after antiretroviral
therapy. Jpn J Infect Dis 2013;66(6):469–74.
178. Colgate ER, Haque R, Dickson DM, Carmolli MP, Mychaleckyj JC,
Nayak U, Qadri F, Alam M, Walsh MC, Diehl SA, et al. Delayed dosing
of oral rotavirus vaccine demonstrates decreased risk of rotavirus
gastroenteritis associated with serum zinc: a randomized controlled
trial. Clin Infect Dis 2016;63(5):634–41.
179. Lazarus RP, John J, Shanmugasundaram E, Rajan AK, Thiagarajan S,
Giri S, Babji S, Sarkar R, Kaliappan PS, Venugopal S, et al. The eect of
probiotics and zinc supplementation on the immune response to oral
rotavirus vaccine: a randomized, factorial design, placebo-controlled
study among Indian infants. Vaccine 2018;36(2):273–9.
180. Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A,
Khatun F, Martorell R, Ninh NX, Penny ME, et al. Therapeutic eects
of oral zinc in acute and persistent diarrhea in children in developing
countries: pooled analysis of randomized controlled trials. Am J Clin
Nutr 2000;72(6):1516–22.
181. Habib MA, Soo S, Sheraz A, Bhatti ZS, Okayasu H, Zaidi
SZ,MolodeckyNA,PallanschMA,SutterRW,BhuttaZA.
Zinc supplementation fails to increase the immunogenicity of
oral poliovirus vaccine: a randomized controlled trial. Vaccine
2015;33(6):819–25.
182. Afsharian M, Vaziri S, Janbakhsh AR, Sayad B, Mansouri F,
Nourbakhsh J, Qadiri K, Naja F, Shirvanii M. The eect of zinc
sulfate on immunologic response to recombinant hepatitis B vaccine
in elderly. Hepat Mon 2011;11(1):33–6.
183. Provinciali M, Montenovo A, Di Stefano G, Colombo M, Daghetta L,
Cairati M, Veroni C, Cassino R, Della Torre F, Fabris N. Eect ofzinc or
zinc plus arginine supplementation on antibody titre and lymphocyte
subsets after inuenza vaccination in elderly subjects: a randomized
controlled trial. Age Ageing 1998;27(6):715–22.
184. Osendarp SJM, Prabhakar H, Fuchs GJ, van Raaij JMA, Mahmud H,
Tofail F, Santosham M, Black RE. Immunization with the heptavalent
pneumococcal conjugate vaccine in Bangladeshi infants and eects of
zinc supplementation. Vaccine 2007;25(17):3347–54.
185. Albert MJ, Qadri F, Wahed MA, Ahmed T, Rahman ASMH, Ahmed F,
BhuiyanNA,ZamanK,BaquiAH,ClemensJD,etal.Supplementation
with zinc, but not vitamin A, improves seroconversion to vibriocidal
antibody in children given an oral cholera vaccine. J Infect Dis
2003;187(6):909–13.
Zinc as an antiviral 15
Downloaded from https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmz013/5476413 by Sydney College of Arts user on 23 April 2019
... Zinc is the second most common trace element that is vital for the growth, development, and maintenance of immune function, in addition to its critical role in antiviral immunity. Its influence reaches all organs and cell types, representing an essential component of approximately 10% of the human proteome and encompassing hundreds of key enzymes and transcription factors [2,3]. Many foods are considered rich in zinc including meat, poultry, shellfish, legumes, nuts, eggs, and dairy products [4]. ...
... Several surveys conducted have claimed that zinc consumption is likely to reduce the intensity of COVID-19 infection due to its antiviral properties; it also helps to alleviate respiratory tract infections [3,15]. ...
Article
Full-text available
Background Zinc is an anti-inflammatory and antioxidant micronutrient found in food. Due to its well-established role in immunity, it is currently being used in some clinical trials against coronavirus disease-2019 (COVID-19). This study aimed to assess the association between the mean serum zinc level in COVID-19 Egyptian patients and its relationship with disease severity. This cross-sectional study was conducted on sixty patients with confirmed COVID-19 infection. These patients were divided into two groups according to clinical outcome, group 1 which included 30 intensive care unit (ICU) patients and group 2 which included 30 patients who were admitted to the ward. Mean serum levels of zinc were compared between the two groups. Results There was a statistically significant difference noted among study groups regarding the serum zinc level ( p < 0.039), where lower mean serum zinc levels were noted in ICU patients compared to ward patients (70.6 ± 5.7 vs 73.8 ± 6.1). Conclusion Low serum zinc level is associated with the severe outcome of COVID-19 infection.
... Zinc not only plays an important role in functioning and development of macrophages, T and B-lymphocytes and immunoglobulins but also in hindering the replication of RNA virus including SARS-CoV [64]. The deficiency of zinc is known to hinder the process of phagocytosis, production of T lymphocytes, activities of natural killer cells, complement activity, reduced functioning of T and B lymphocyte [65] and augments production of inflammatory cytokines (Figure 2). The barriers such as the epidermis is affected and also the respiratory and gastrointestinal mucosa is damaged during zinc deficiency [66]. ...
Article
Coronavirus has held humanity hostage since 2020 and its dominance continues with emerging variants. Although various medications and vaccines are available world-wide but none can prevent the disease, focusing our attention to modalities which can help in strengthening the immune system. The fact of the matter is the COVID-19 infection hampers the immune system through various inflammatory responses. Hence, the need of the hour is to emphasise on balanced diet which includes vitamins along with macro and micronutrients which would be beneficial in prevention of various infections. The paper discusses the available data on the role of minerals and vitamins in the COVID-19 treatment. The functioning of immune system is compromised when the vitamins and mineral content are deficient. The minerals and vitamins can be used as preventive measures to reduce the mortality and morbidity rates in patients with the viral infection.
... Zinc can also directly regulate kinases, phosphatases, or channel activities (Pan et al., 2017). Moreover, Zn exhibits anti-oxidative and anti-inflammatory properties; its deficiency leads to growth disorders, anemia, neuronal dysfunctions, as well as cardiovascular diseases (Read et al., 2019). Zn concentrations in mushrooms have been analyzed in many publications, its level often ranges of 50-150 mg kg − 1 (Świsłowski et al., 2020). ...
Article
Full-text available
Phragmites australis (common reed) distributed in brackish or saline wetlands, with significant ecological and economic values. Cultivating edible fungi is an exciting and developing field in reed utilization, and proven to be a viable technology. However, it remains unclear how nutrient utilization efficiency differs between mushroom species. Globally, Pleurotus ostreatus is the easily and most bagged cultivated mushroom. Therefore, three Pleurotus species were used to investigate the nutrient utilization of reed. A 2-year cultivation experiment was conducted during which three mushroom flushes were obtained. A significant difference in fresh weight was only found in the first harvest of the three mushroom species. A comparison of fruit quality characteristics of the first flush revealed the highest levels to be as follows, respectively: fresh weight in P. ostreatus (57.4%), total sugar content in P. eryngii (69.0%), and crude protein (28.3%) and amino acids levels in P. citrinopileatus. Glusate and histidine were the main amino acid components in P. citrinopileatus. Besides, iron and zinc could be heavily enriched in P. ostreatus. Heavy metals were the highest in P. ostreatus, but they were below the National Food Safety Standards. Generally, P. ostreatus had the highest biological efficiency, while P. eryngii had the highest carbon utilization and P. citrinopileatus had the highest nitrogen utilization efficiency.
... This mineral can also improve the integrity and barrier function of the respiratory epithelium by increasing its antioxidant activity and upregulating its tight junction proteins such as claudin-1 and zonula occludens-1 (Skalny et al., 2020). In addition, zinc may exert antiviral effects through interference with viral replication cycles (Read et al., 2019). Moreover, zinc can be beneficial for bacterial coinfection in viral pneumonia, because it may inhibit the growth of Streptococcus pneumoniae by modulating bacterial manganese homeostasis (Eijkelkamp et al., 2019). ...
Article
Full-text available
Coronavirus disease 2019 (COVID‐19) is a newly emerging viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Oxidative stress appears to be a prominent contributor to the pathogenicity of SARS‐CoV‐2. Therefore, we carried out a systematic review of human observational and interventional studies to investigate the role of some antioxidants such as vitamins A, E, D, and C, selenium, zinc, and α‐lipoic acid in the main clinical outcomes of subjects with COVID‐19. Google Scholar, Cochrane Library, Web of Science, Scopus, and Medline were searched using Medical Subject Headings (MeSH) and non‐MeSH terms without restrictions. Finally, 36 studies for vitamins C and D, selenium, and zinc were included in this systematic review; however, no eligible studies were found for vitamins A and E as well as α‐lipoic acid. The results showed the promising role of vitamin C in inflammation, Horowitz index, and mortality; vitamin D in disease manifestations and severity, inflammatory markers, lung involvement, ventilation requirement, hospitalization, intensive care unit (ICU) admission, and mortality; selenium in cure rate and mortality; and zinc in ventilation requirement, hospitalization, ICU admission, biomarkers of inflammation and bacterial infection, and disease complications. In conclusion, it seems that antioxidants, especially vitamins C and D, selenium, and zinc, can improve multiple COVID‐19 clinical outcomes. Nevertheless, more studies are necessary to affirm these results.
... An association between selenium de ciency, immune dysfunction, progression to AIDS, and death has been shown in cohort studies conducted before antiretroviral therapy (ART) in both children and adults (11,12). Zinc is an antioxidant and immune modulator and may have antiviral effects as zinc de cient populations are at higher risk of acquiring viral infections (13). In adults living with HIV, low levels of serum zinc have been associated with more advanced HIV disease and increased mortality independent of baseline CD4 count (14). ...
Preprint
Full-text available
Background: Micronutrient deficiencies due to malabsorption, gut infections, and altered gut barrier function are common in children living with HIV (CLHIV) and may worsen with severe acute malnutrition (SAM). Methods: This secondary analysis of IMPAACT P1092, a Phase IV, multicenter, open label, non-randomized study of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) pharmacokinetics, safety, and tolerability enrolled SAM and non-SAM CLHIV age 6 to <36 months. Children initiated WHO recommended nutritional rehabilitation prior to enrollment when indicated at screening and were stratified by nutritional status and followed for 48 weeks. Zinc, selenium, serum protein and albumin were measured at entry and week 48 with albumin and total protein serum also measured at weeks 8 and 16. Results Fifty-two participants, 25 SAM and 27 non-SAM, of median (Q1,Q3) age 19 (13,25) and 18 (12,25) months respectively, were enrolled. Zinc deficiency was present at entry in 2/27 (8%) from the SAM cohort. Mean (SD) baseline zinc levels for the SAM and non-SAM cohort [52.2(15.3), 54.7(12.2) µg/dL] and selenium [92.9(25.0), 84.3(29.2) µg/L] were similar, and there was no difference in change from study entry to week 48 for both: mean (95% CI) difference SAM minus non-SAM of -0.3 (-11.2,10.5) µg/dL and -5.1 (-20.1,9.8) µg/L for zinc and selenium respectively. Mean (SD) baseline total protein levels [75.2(13.2), 77.3(9.4) g/L] and mean change from entry to 48 weeks were similar between cohorts (mean difference (95% CI) (4.6 (-2.4,11.6). The SAM cohort had significantly lower serum albumin levels at entry compared to the non-SAM cohort (mean difference (95% CI) 6.2 (-10.1, -2.4) g/L) and levels were similar after 48 weeks (mean difference (95% CI) 0.4 (-2.2, 2.9) g/L). Mean increase in albumin at 48 weeks was greater in the SAM cohort (mean difference (95% CI) 6.3 (1.9, 10.7) g/L). Conclusions These children who were on highly active combination antiretroviral therapy and had malnutrition showed normal levels of selenium and zinc after 10-18 days of nutritional rehabilitation. Entry albumin levels were lower in SAM compared to non-SAM, with normalization to non-SAM levels by 48 weeks. Total protein levels were similar at entry and week 48. Trial Registration The study was registered with ClinicalTrials.gov Identifier NCT01818258 26/03/2013
Article
Objective Zinc and selenium levels are being investigated with increasing frequency in adult patients with coronavirus disease 2019 (COVID-19). However, levels of zinc and selenium in children with COVID-19 have not been adequately studied to date. Methods This prospective, observational study was conducted on 146 pediatric patients diagnosed with COVID-19 and 49 healthy controls between 2020 and 2021. Normal serum zinc reference values were 0.60 to 1.20 µg/mL for children 0 to 10 years old and 0.66 to 1.10 µg/mL for children ≥11 years old. The normal range for serum selenium concentration was considered between 70 and 150 µg/L. Deficiencies were defined for values below the reference range. Results Zinc and selenium levels were significantly lower in the COVID-19 (+) group compared with the controls (zinc: 0.7 ± 0.2 vs 0.9 ± 0.2 µg/mL, p < 0.001; selenium: 57.1 ± 9.1 vs 66.5 ± 11.4 µg/L, p < 0.01, respectively). Also, zinc and selenium levels were found to be statistically significantly lower in the hospitalized group compared with the outpatient group (zinc: 0.6 ± 0.2 vs 0.8 ± 0.2 µg/mL, p < 0.001; selenium: 52.1 ± 9.6 vs 58.8 ± 8.3 µg/L, p < 0.001). In the receiver operating characteristic curve analysis, selenium levels with a cutoff value of 55.50 µg/L, with 75% sensitivity and 70% specificity, and zinc levels with a cutoff value of 0.7 µg/mL, with 56% sensitivity and 53% specificity, predicted hospitalization. Conclusion Our data showed that serum zinc and selenium levels were significantly lower in patients with COVID-19 compared with healthy control group. Also, zinc and selenium levels were found to be lower in the hospitalized group compared with the outpatient COVID-19 group.
Article
Viral pathologies encompass activation of pro-oxidative pathways and inflammatory burst. Alleviating overproduction of reactive oxygen species and cytokine storm in COVID-19 is essential to counteract the immunogenic damage in endothelium and alveolar membranes. Antioxidants alleviate oxidative stress, cytokine storm, hyperinflammation, and diminish the risk of organ failure. Direct antiviral roles imply: impact on viral spike protein, interference with the ACE2 receptor, inhibition of dipeptidyl peptidase 4, transmembrane protease serine 2 or furin, and impact on of helicase, papain-like protease, 3-chyomotrypsin like protease, and RNA-dependent RNA polymerase. Prooxidative environment favors conformational changes in the receptor binding domain, promoting the affinity of the spike protein for the host receptor. Viral pathologies imply a vicious cycle, oxidative stress promoting inflammatory responses, and vice versa. The same was noticed with respect to the relationship antioxidant impairment-viral replication. Timing, dosage, pro-oxidative activities, mutual influences, and interference with other antioxidants should be carefully regarded. Deficiency is linked to illness severity.
Article
The pandemic of COVID-19 was caused by a novel coronavirus termed as SARS-CoV2 and is still ongoing with high morbidity and mortality rates in the whole world. The pathogenesis of COVID-19 is highly linked with over-active immune and inflammatory responses, leading to activated cytokine storm, which contribute to ARDS with worsen outcome. Currently, there is no effective therapeutic drug for the treatment of COVID-19. Zinc is known to act as an immune modulator, which plays an important role in immune defense system. Recently, zinc has been widely considered as an anti-inflammatory and anti-oxidant agent. Accumulating numbers of studies have revealed that zinc plays an important role in antiviral immunity in several viral infections. Several early clinical trials clearly indicate that zinc treatment remarkably decreased the severity of the upper respiratory infection of rhinovirus in humans. Currently, zinc has been used for the therapeutic intervention of COVID-19 in many different clinical trials. Several clinical studies reveal that zinc treatment using a combination of HCQ and zinc pronouncedly reduced symptom score and the rates of hospital admission and mortality in COVID-19 patients. These data support that zinc might act as an anti-viral agent in the addition to its anti-inflammatory and anti-oxidant properties for the adjuvant therapeutic intervention of COVID-19.
Article
During the coronavirus disease 2019 (COVID-19) pandemic and continuing emergence of viral mutants, there has been a lack of effective treatment methods. Zinc maintains immune function, with direct and indirect antiviral activities. Zinc nutritional status is a critical factor in antiviral immune responses. Importantly, COVID-19 and zinc deficiency overlap in high-risk population. Hence, the potential effect of zinc as a preventive and adjunct therapy for COVID-19 is intriguing. Here, this review summarizes the immune and antiviral function of zinc, the relationship between zinc levels, susceptibility, and severity of COVID-19, and the effect of zinc supplementation on COVID-19. Existing studies have confirmed that zinc deficiency was associated with COVID-19 susceptibility and severity. Zinc supplementation plays a potentially protective role in enhancing immunity, decreasing susceptibility, shortening illness duration, and reducing the severity of COVID-19. We recommend that zinc levels should be monitored, particularly in COVID-19 patients, and zinc as a preventive and adjunct therapy for COVID-19 should be considered for groups at risk of zinc deficiency to reduce susceptibility and disease severity.
Article
A dual‐functional anti‐pathogenic coating with controllable repelling and capturing/inactivation of pathogens, which make it capable of eliminating a broad range of pathogenic bacteria and viruses, including SARS‐CoV‐2, is reported. The reversible switch between repelling and capturing/inactivation is readily made via its CO2‐responsive wettability. In its superhydrophobic state, the coating enables a SARS‐CoV‐2 repellent efficacy of 99.9997%. In its superhydrophilic state, the coating has a virucidal efficacy of up to 99.9897%, which is comparable to the inactivation rate of chemical disinfectants. The coating is highly flexible with anti‐corrosive and anti‐frosting properties, which works for repelling essentially all pathogens and potentially could be applied into various daily used products and materials. The coating has the potential to set a new prevention standard in fighting the current pandemic and preventing future ones via especially intercepting the transmission of pathogens through contaminated surfaces. Dual‐functional anti‐pathogen coatings selectively repel or capture/inactivate pathogenic bacteria and viruses, including SARS‐CoV‐2. The coating exhibits a highly effective performance against SARS‐CoV‐2 with a virus‐repellent efficiency of up to 99.9997% and a virucidal efficacy of 99.9897%, which can be applied into various daily used products and materials.
Article
Full-text available
Zinc (Zn) is an essential trace element which has favorable antioxidant, anti-inflammatory, and apoptotic effects. The liver mainly plays a crucial role in maintaining systemic Zn homeostasis. Therefore, the occurrence of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, or fatty liver, results in the impairment of Zn metabolism, and subsequently Zn deficiency. Zn deficiency causes plenty of metabolic abnormalities, including insulin resistance, hepatic steatosis and hepatic encephalopathy. Inversely, metabolic abnormalities like hypoalbuminemia in patients with liver cirrhosis often result in Zn deficiency. Recent studies have revealed the putative mechanisms by which Zn deficiency evokes a variety of metabolic abnormalities in chronic liver disease. Zn supplementation has shown beneficial effects on such metabolic abnormalities in experimental models and actual patients with chronic liver disease. This review summarizes the pathogenesis of metabolic abnormalities deriving from Zn deficiency and the favorable effects of Zn administration in patients with chronic liver disease. In addition, we also highlight the interactions between Zn and other trace elements, vitamins, amino acids, or hormones in such patients.
Article
Full-text available
Metallothioneins (MTs) are small, cysteine rich proteins characterized by a high affinity for monovalent and divalent cations, such as copper and zinc. Of the four known metallothionein isoforms, only members of the metallothionein 1 and 2 subfamilies are widely expressed, acting as metal chaperones whose primary role is to mediate intracellular zinc homeostasis. Metallothioneins are potently induced by heavy metals and other sources of oxidative stress where they facilitate metal binding and detoxification as well as free radical scavenging. Metallothionein expression is well documented in the context of viral infection, however it remains uncertain whether metallothioneins possess specific antiviral roles or whether induction is merely a consequence of cellular stress. To better understand the role of metallothioneins following hepatitis C virus (HCV) infection, we examined metallothionein expression and localisation in vitro and in vivo, and used a siRNA knockdown approach to ascertain their antiviral efficacy. We confirmed HCV driven metallothionein induction in vitro, and demonstrated metallothionein accumulation in the nucleus of HCV infected hepatocytes by immunofluorescence. Using a pan-metallothionein siRNA to knock down all members of the MT1 and 2 subfamilies we demonstrate that they are mildly antiviral against the JFH1 strain of HCV in vitro (~1.4 fold increase in viral RNA, p<0.05). Furthermore, the antiviral effect of zinc treatment against HCV in vitro was mediated through metallothionein induction (p<0.05). Our data suggest a potential benefit of using zinc as a low-cost adjunct to current HCV antiviral therapies, and suggests that zinc may facilitate the antiviral role of metallothioneins against other viruses.
Article
Full-text available
Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as “zinc waves”, and late homeostatic zinc signals regarding prolonged changes in intracellular zinc.
Article
Full-text available
Metallothioneins (MTs) are a family of metal-binding proteins virtually expressed in all organisms including prokaryotes, lower eukaryotes, invertebrates and mammals. These proteins regulate homeostasis of zinc (Zn) and copper (Cu), mitigate heavy metal poisoning, and alleviate superoxide stress. In recent years, MTs have emerged as an important, yet largely underappreciated, component of the immune system. Innate and adaptive immune cells regulate MTs in response to stress stimuli, cytokine signals and microbial challenge. Modulation of MTs in these cells in turn regulates metal ion release, transport and distribution, cellular redox status, enzyme function and cell signaling. While it is well established that the host strictly regulates availability of metal ions during microbial pathogenesis, we are only recently beginning to unravel the interplay between metal-regulatory pathways and immunological defenses. In this perspective, investigation of mechanisms that leverage the potential of MTs to orchestrate inflammatory responses and antimicrobial defenses has gained momentum. The purpose of this review, therefore, is to illumine the role of MTs in immune regulation. We discuss the mechanisms of MT induction and signaling in immune cells and explore the therapeutic potential of the MT-Zn axis in bolstering immune defenses against pathogens.
Article
Transcription factors (TFs) recognize specific DNA sequences to control chromatin and transcription, forming a complex system that guides expression of the genome. Despite keen interest in understanding how TFs control gene expression, it remains challenging to determine how the precise genomic binding sites of TFs are specified and how TF binding ultimately relates to regulation of transcription. This review considers how TFs are identified and functionally characterized, principally through the lens of a catalog of over 1,600 likely human TFs and binding motifs for two-thirds of them. Major classes of human TFs differ markedly in their evolutionary trajectories and expression patterns, underscoring distinct functions. TFs likewise underlie many different aspects of human physiology, disease, and variation, highlighting the importance of continued effort to understand TF-mediated gene regulation.
Article
Background: Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. Methods: Infants 5weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5mg), probiotic (10(10)Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at ≥20U/ml in previously seronegative infants or a fourfold rise in concentration. Results: The study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): -1.4%, 16.2%), p=0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: -4.4%, 13.2%), p=0.272). 16 serious adverse events were recorded, none related to study interventions. Conclusions: Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation. Trial registration: The trial was registered in India (CTRI/2012/05/002677).
Article
Human papillomavirus (HPV)-induced cancers are expected to remain a major health problem worldwide for decades. The growth of HPV-positive cancer cells depends on the sustained expression of the viral E6 and E7 oncogenes which act in concert with still poorly defined cellular alterations. E6/E7 constitute attractive therapeutic targets since E6/E7 inhibition rapidly induces senescence in HPV-positive cancer cells. This cellular response is linked to the reconstitution of the antiproliferative p53 and pRb pathways, and to prosenescent mTOR signaling. Hypoxic HPV-positive cancer cells could be a major obstacle for treatment strategies targeting E6/E7 since they downregulate E6/E7 but evade senescence through hypoxia-induced mTOR impairment. Prospective E6/E7 inhibitors may therefore benefit from a combination with treatment strategies directed against hypoxic tumor cells.
Article
We previously showed that the combination of the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 with zinc acetate (ZA) formulated in a carrageenan (CG; MZC) gel provided macaques significant protection against vaginal simian-human immunodeficiency virus-RT (SHIV-RT) challenge, better than either MIV-150/CG or ZA/CG. The MZC gel was shown to be safe in a phase 1 clinical trial. Herein, we used in vitro approaches to study the antiviral properties of ZA and the MIV-150/ZA combination, compared to other NNRTIs. Like other NNRTIs, MIV-150 has EC50 values in the subnanomolar to nanomolar range against wild type and NNRTI or RT-resistant HIVs. While less potent than NNRTIs, ZA was shown to be active in primary cells against laboratory-adapted and primary HIV-1 isolates and HIV-1 isolates/clones with NNRTI and RT resistance mutations, with EC50 values between 20 and 110 μM. The MIV-150/ZA combination had a potent and broad antiviral activity in primary cells. In vitro resistance selection studies revealed that previously described NNRTI-resistant mutations were selected by MIV-150. ZA-resistant virus retained susceptibility to MIV-150 (and other RTIs) and MIV-150-selected virus remained sensitive to ZA. Notably, resistant virus was not selected when cultured in the presence of both ZA and MIV-150. This underscores the potency and breadth of the MIV-150/ZA combination, supporting preclinical macaque studies and the advancement of MZC microbicides into clinical testing.