Biomedical Engineering & Biosciences - Juniper Publishers

Anti-viral vaccine activity of Zn2+ ions for viral
prevention, pathogenesis processes, and ROS generation causing to
oxidative stress have been investigated. AZP is efficient for viral
prevention by inhibitions of BSCTV and DNA virus replications. The AZP
phenotypes show strongly resistant to virus infection and viral DNA
replication could be applied to the prevention of virus infections in
humans. ZnOTs exhibit the ability to neutralize HSV-2 virions and
blocking HSV-2 attachment activity. Zinc salts can mediate antiviral
activity on RSV by altering the ability of the cell to support RSV
replication. The effect of zinc sulfate on seroconversion after a simple
method vaccination had been identified that accelerated HB vaccination
can shorten duration of immunization of this clinical trial for showing
its effectiveness. The inhibition of zinc binding activity of hMPV M2-1
protein can lead to the development of novel, live attenuated vaccines
as well as antiviral drugs for pneumoviruses. The CCHH zinc finger motif
provides potential vaccine candidates for the development of live
species-specific attenuated influenza virus vaccines. Chelates zinc ions
inhibit HIV-1 replication. The LAIVs are attracting attention as
several advantages over inactivated vaccines. Zinc finger reactive
compounds also inactivate retroviruses. ZOTEN promoted the presentation
of bound HSV-2 virions.
The regulated ZFNs in the presence of HIV-1 Tat may
provide a safer and novel genome-editing technology for eradicating
HIV-1 proviral DNA from infected host cells. Zinc ions inhibit vaccine
virus growth. The ZAP inhibits HIV-1 infection by viral mRNAs
degradation. ZAP also inhibits the spreading against XMRV. The treatment
of viral infections with viral spreading will be achieved and improved
the therapeutic effects by using zinc oxide nanoparticles. ROS and RNS
within viruses of viral entry, viral replication, and viral spread are
generated in all situations. ROS in virus pathogenesis play an important
role in cell signaling and regulate hormone action, growth factors,
cytokines, transcription, apoptosis, immunomodulation, and
neuromodulation, leading to chronic oxidative stress. Oxidative stress
has been occurred in various viral infections. The antioxidant
components lead to an excess storage of H2O2, which further increases
the hydroxyl radicals and lipid peroxide that signal the cell to undergo
a programmed cell death. Thus, zinc-associated vaccine activity
mechanism against viruses is indicated that the anti-viral vaccine
activity of released Zn2+ ions from zinc solutions and ZnO NPs, may be
enhanced by Zn2+ ion-induced Zn2+ ions-coordinated adapted immunity,
viral growth regulation, and viral apoptosis and death.
Keywords: AZP/ZOTEN/ZAP/ZFN; Zinc salts and zinc sulfate; ROS; Oxidative stress; HIV/hMPV/ LAV/RSV/XMRV
Abbreviations: APCs:
Antigen Presenting Cell; AZP: Artificial Zinc Finger Protein; BSCTV:
Beet Severe Curly Top Virus; HIV: Human Immunodeficiency Virus; hMPV:
Human Metapneumovirus; HBV: Hepatitis B Virus; HEV: Hepatitis E Virus;
HSV2: Herpes Simplex Virus Type-2; IRF3: Interferon Regulatory Factor 3;
ISREs: Interferon Stimulated Response Elements; LAIVs: Live Attenuated
Influenza Vaccines; LAV: Live Attenuated Virus; NKT: Natural Killer T;
PLZF: Promyelocytic Leukemia Zinc Finger; RdRp: RNA-Dependent RNA
Polymerase; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen
Species; RSV: Respiratory Syncytial Virus, SSP: Stable Signal Peptide;
TALENs: Transcription Activator-Like Effector Nucleases; XMRV:
Xenotropic Murine Leukemia Virus related Virus; ZBD: Zinc-Binding
Domain; ZAP: Zinc-Finger Antiviral Protein; ZFN: Zinc Finger Nuclease;
ZnOTs: ZINC OXIDE TETRAPODS; ZOTENs: Zinc Oxide Tetrapod Nanoparticles
Viruses are small protein capsid that harbor genetic
information. In the case of enveloped viruses, an additional lipid
bilayer surrounds the capsid that enveloped viruses can spread via two
distinct routes, either through the cell-free aqueous environment or,
alternatively, by remaining cell associated and being passed on by
direct cell-cell contact [1].
The other, zinc is the second most abundant trace
metal with human body 2-3g, 90% in muscle and bone, and 10% other organs
include prostate, liver, the gastrointestinal tract, kidney, skin, lung
brain, heart, and pancreas in humans which cellular zinc underlies an
efficient homeostatic control that avoids accumulation of zinc in excess
[2]. The role of zinc in cell death has apoptosis that the influence of
zinc on apoptosis is tissue/
cell type, zinc concentration, and expression of zinc transporters
and zinc-binding proteins [2]. Zinc has a rather low toxicity and
influences apoptosis by acting on several molecular regulators
of programmed cell death, including caspases and proteins from
the Bcl and Bax families.
Zinc induced anti-virus activity may be enhanced for Tcell
division, maturation and differentiation, lymphocyte response
to mitogens, programmed cell death of lymphoid and myeloid
origins, gene transcription, and biomembrane function [3]. Nonstructure
NS5A is a zinc metalloprotein and zinc coordination is
likely required for NS5A function in the hepatitis C replicase that
reduced NS5A zinc coordination and zinc binding motif were
tolerated for replication [4]. The zinc-finger antiviral protein
(ZAP) induced virus during viral infection little is known,
however, mutational analysis of the human ZAP promoter
revealed that multiple interferon stimulated response elements
(ISREs) distal to the transcription start site serve redundantly
to control interferon regulatory factor 3 (IRF3)-dependent
induction of ZAP trancription [5].
Anti-virus vaccine principle is to viral prevention and devoid
serious diseases that live attenuated virus (LAV) vaccines have
provided ideal protection from several major diseases. The
ability to create a zinc finger nuclease (ZFN) vaccine that can
prevent and eliminate persistent viral infections is a long way
from being realized, in which the efficacies by available LAV, live
attenuated rotavirus, influenza, and varicella zoster vaccines
are strong incentive to redouble efforts to improve the safety
characteristics of this type of vaccine [6]. Vaccines for numerous
infectious diseases have been developed using whole inactivated
virions that live attenuated influenza vaccines (LAIVs) are
particularly attracting attention as effective strategy due to
several advantages over inactivated vaccines [7].
Zinc-binding activity of human metapneumovirus (M21)
protein was found to incorporate zinc ions, although the
specific roles of the zinc binding activity in viral replication
and pathogenesis remains unclear [8]. The pathogenic process,
namely viral pathogenesis is the process by which an infection
leads to disease that pathogenic mechanisms of viral disease
include viral entry, local replication, and spread to organs and
shedding of disease site [9]. Accordingly, the zinc induced Zn2+
ion coordinated activity results in regulation of viral growth
and may lead to virus death in host cell-virus interaction during
pathogenesis process.
In this review, zinc-mediated anti-viral vaccine activities have
been investigated for viral prevention, viral entry, replication/
DNA/RNA virus, and spreading to organs during pathogenesis
process. Lastly, ROS productions and leading to oxidative stress
and virus death are discussed.
Viral prevention is a major objective in human health. One
attractive approach to the prevention is inhibition of virus
replication. Artificial zinc finger proteins (AZP) have been
targeted to the replication origin of the Beet severe curly top
virus (BSCTV), a model DNA virus that the AZP efficiently
blocked binding of the viral replication protein, which initiates
virus replication, to the replication origin. These results showing
to the AZP phenotypes strongly resistant to virus infection and
viral DNA replication could be applied to the prevention of virus
infections in humans [10]. Inhibition of virus DNA replication
by AZP is comparable to viral prevention. Zinc oxide tetrapods
(ZnOTs) exhibit the ability to neutralize herpes simplex virus
type-2 (HSV-2) virions and blocking HSV-2 attachment activity by
ZnOTs can have prophylactic as well as therapeutic applications
[11].
Zinc salts was examined in the presence of zinc during
preincubation, adsorption, or penetration by the degree of
inhibition of respiratory syncytial virus (RSV) replication, the
resulting that zinc can mediate antiviral activity on RSV by
altering the ability of the cell to support RSV replication [12].
Further, zinc salts did not show any effect on the entry of g-1
hepatitis E virus (HEV) into the host cell, directly inhibit the
activity of the viral RNA-dependent RNA polymerase (RdRp),
leading to inhibition of viral replication, suggesting their
possible therapeutic value in controlling HEV infection [13].
The other, Zinc sulfate has no effect in level of immunity among
elderly and zinc may stimulate antibody response in the nonresponders
to recombinant hepatitis B vaccine. The effect of zinc
sulfate on seroconversion after a simple method vaccination
had been identified that accelerated hepatitis B vaccination
can shorten duration of immunization of this clinical trial for
showing its effectiveness [14]. The inhibition of zinc binding
activity of human metapneumovirus (hMPV) M2-1 protein can
lead to the development of novel, live attenuated vaccines as
well as antiviral drugs for pneumoviruses [8].
The CCHH zinc finger motif provides a critical determinant
for virulence in mouse and mutations in the CCHH motif yield
potential vaccine candidates for the development of live speciesspecific
attenuated influenza virus vaccines [15]. Chelates zinc
ions (a bisthiadiazolbenzene-1,2-diamine) from retroviral
nucleocapsid zinc fingers inhibit HIV-1 replication [16]. This
compound thus acts via a different mechanism than the
previously reported zinc ejectors, as its structural features do not
allow an acyl transfer to Cys or a thioldisulfide interchange. The
cleaved stable signal peptide (SSP) is retained in GPC through
interaction with a zincbinding domain (ZBD) in the cytoplasmic
tail of G2 [17]. The live attenuated influenza vaccines (LAIVs)
are attracting attention as an effective strategy due to several advantages over inactivated vaccines [18]. Zinc finger reactive
compounds also inactivate retroviruses by targeting the zinc
finger motif in their nucleocapsid proteins. These compounds
are effective against respiratory syncytial virus (RSV) that AT-
2-inactivated RSV vaccine may not be enough to produce a
highly efficacious inactivated virus vaccine which does not lead
to an atypical disease [19]. Intravaginal zinc oxide tetrapod
nanoparticles (ZOTEN) promoted the presentation of bound
HSV-2 virions to mucosal APCs, enhancing T cell-mediated and
Ab-mediated responses to the infection, and thereby suppressing
a reinfection [20].
A human papillomavirus type 16 E7 DNA vaccine indicated
a significantly stronger E7-specific cytotoxic T-lymphocyte
induction and better antitumor protection [21]. Zinc finger
nucleases (ZFNs) can specifically and efficiently excise HIV-1
proviral DNA from latently infected human T cells, the resulting
from HIV-1infected human primary T cells and latently infected T
cells treated with the inducible ZFNs validated that proviral DNA
can be excised [22]. The regulated ZFNs in the presence of HIV-1
Tat may provide a safer and novel genome-editing technology
for eradicating HIV-1 proviral DNA from infected host cells. ZFNs
and transcription activator-like effector nucleases (TALENs)
bear sequence-specific DNA-binding modules that recognize
HIV DNA sequences [23]. Therapeutic potential of ZFNs and
zinc finger arrays (ZFAs) is confirmed with unique specificity to
HSV-2 the genome which ZFNs with specificity to HSV-2 genomic
DNA are precursors of novel host genome expressed HSV-2
gene-therapeutics or vaccines [24]. Zinc supplementation in
cultured HeLa cells inhibits DNA laddering & caspase-3 activity,
and inhibitory effect on influenza virus induced apoptotic
death can be determined at an early stage of the infection by
zinc treatment [25]. Further, zinc ions inhibit vaccine virus
growth, and a fraction of RNA which is normally synthesized
infected cells, was missing from a proper part of the gradient
if the cell were treated with zinc ions within 1 h post infection
that a transcriptional step is involved in zinc-caused inhibition
of vaccinia virus growth [26]. The zinc-finger antiviral protein
(ZAP) inhibits HIV-1 infection by viral mRNAs degradation
that ZAP inhibits HIV-1 by recruiting both the 5’ and 3’ mRNA
degradation to specifically promote the degradation of multiply
spliced HIV-1 mRNA [27].
Higher levels of dietary zinc oxide (ZnO) levels could not
provide enhanced protection against porcine reproductive and
respiratory syndrome virus (PRRSV) vaccine and infection that
have the potential to stimulate or modulate systemic immune
responses after vaccination [28]. In the synthesized ZnO tetrapod
nanoparticles (ZOTENs), ZOTENs prevent HSV-2 infection
and disease that ZOTEN provides a platform for virus capture
and presentation of neutralized virions to mucosal antigen presenting cell (APCs), for initiating and boosting adaptive
immunity which provides the novel evidence for the protective
efficacy of an intravaginal microbicide/vaccine or microbivac
platform against primary and secondary female genital herpes
infection [29].
ZAP inhibits the spreading of replication-competent
xenotropic murine leukemia virus-related virus (XMRV)
which ZAP inhibits viral infection [30]. The treatment of viral
infections with viral spreading will be achieved and improved
the therapeutic effects by using zinc oxide nanoparticles [31].
ROS Generation in Host Cell-Virus Interaction and Leading
to Virus Growth Regulation and Virus Death
Reactive oxygen species (ROS) and reactive nitrogen species
(RNS) within viruses of viral entry, viral replication, and viral
spread are generated in all situations. ROS induce several cellular
effects, including cell cycle progression, apoptosis, DNA damage,
senescence, and neurodegeneration. ROS in virus pathogenesis
play an important role in cell signaling and regulate hormone
action, growth factors, cytokines, transcription, apoptosis,
immunomodulation, and neuromodulation, leading to chronic
oxidative stress [32]. Oxidative stress has been occurred in various
viral infections. For human immunodeficiency virus (HIV), the
body antioxidant system becomes weaker as HIV progresses
that the imbalances inside and outside the cell influence the
cell to undergo a programmed cell death [32]. The antioxidant
components lead to an excess storage of H2O2, which further
increases the hydroxyl radicals and lipid peroxide that signal
the cell to undergo a programmed cell death [32]. The influenza
virus induces ROS production in host cells that can damage the
virus genome which ROS enhance the pathogenesis ability of
infectious influenza that leads to the thymus specific elevation of
the mitochondrial superoxide, which interferes with the normal
functioning of T-cells lymphocyte damage in influenza A virus
infections [32]. Influenza A virus infection causes a rapid influx
of inflammatory cells, resulting in increased ROS production,
cytokine expression, and acute lung injury which inhibition of
this activity would restore host cytokine homeostasis following
avian influenza virus infection [33]. Promyelocytic leukemia zinc
finger (PLZF) controls the ROS levels that in turn PLZF governs
the inflammatory function of natural killer T (NKT) cells, in which
ROS regulate homeostasis and effector function of NKT cells,
both of which are regulated by PLZF [34]. As mentioned above,
anti-viral vaccine activities of Zn2+ ions for viral prevention,
entry, replication, and spreading with pathogenesis process are
exhibited in Table 1. Zinc-associated vaccine activity mechanism
against viruses is indicated that the vaccine activity of released
Zn2+ ions from zinc solutions and ZnO NPs, may be enhanced
by zinc(Ⅱ)-induced Zn2+ coordinated adapted immunity, viral
growth regulation, and viral apoptosis and death
AZP can efficiently block binding of the viral replication
protein, which initiates virus replication, to the replication origin
against BSCTV, DNA virus. The AZP phenotypes show strongly
resistant to virus infection and viral DNA replication could be
applied to the prevention of virus infections in humans. ZnOTs
exhibit the ability to neutralize herpes simplex virus type-2
(HSV-2) virions and blocking HSV-2 attachment activity by ZnOTs
can have prophylactic as well as therapeutic applications. Zinc
salts can mediate antiviral activity on RSV by altering the ability
of the cell to support RSV replication. The effect of zinc sulfate
on seroconversion after a simple method vaccination had been
identified that accelerated HB vaccination can shorten duration
of immunization of this clinical trial for showing its effectiveness.
The inhibition of zinc binding activity of hMPV M2-1 protein can
lead to the development of novel, live attenuated vaccines as
well as antiviral drugs for pneumoviruses. The CCHH zinc finger
motif provides a critical determinant for virulence in mouse and
mutations in the CCHH motif yield potential vaccine candidates
for the development of live species-specific attenuated influenza
virus vaccines. Chelates zinc ions also inhibit HIV-1 replication.
The LAIVs are attracting attention as an effective strategy due to
several advantages over inactivated vaccines. Zinc finger reactive
compounds also inactivate retroviruses. ZOTEN promoted the
presentation of bound HSV-2 virions to mucosal APCs, enhancing
T cell-mediated and Ab-mediated responses to the infection, and
thereby suppressing a reinfection.
ZFNs can specifically and efficiently excise HIV-1 proviral
DNA from latently infected human T cells, the resulting from
HIV-1-infected human primary T cells and latently infected T
cells treated with the inducible ZFNs validated that proviral DNA
can be excised. The regulated ZFNs in the presence of HIV-1 Tat
may provide a safer and novel genome-editing technology for
eradicating HIV-1 proviral DNA from infected host cells. Zinc
supplementation in cultured HeLa cells inhibits DNA laddering
& caspase-3 activity, and inhibitory effect on influenza virus
induced apoptotic death can be determined at an early stage of the infection by zinc treatment. Further, zinc ions inhibit
vaccine virus growth, and are involved in zinc-caused inhibition
of vaccinia virus growth. The ZAP inhibits HIV-1 infection by
viral mRNAs degradation that ZAP inhibits HIV-1 by recruiting
both the 5’ and 3’ mRNA degradation to specifically promote
the degradation of multiply spliced HIV-1 mRNA. Higher levels
of dietary ZnO could not provide enhanced protection against
PRRSV vaccine that higher levels of dietary ZnO have the
potential to stimulate or modulate systemic immune responses
after vaccination against PRRSV. ZOTEN provides a platform for
virus capture and presentation of neutralized virions to mucosal
APCs.
ZAP inhibits the spreading against XMRV which ZAP
inhibits viral infection. The treatment of viral infections with
viral spreading will be achieved and improved the therapeutic
effects by using zinc oxide nanoparticles. ROS and RNS within
viruses of viral entry, viral replication, and viral spread are
generated in all situations. ROS induce several cellular effects,
including cell cycle progression, apoptosis, DNA damage,
senescence, and neurodegeneration. ROS in virus pathogenesis
play an important role in cell signaling and regulate hormone
action, growth factors, cytokines, transcription, apoptosis,
immunomodulation, and neuromodulation, leading to chronic
oxidative stress. Oxidative stress has been occurred in various
viral infections. The body antioxidant system becomes weaker
as HIV progresses that the imbalances inside and outside the
cell influence the cell to undergo a programmed cell death. The
antioxidant components lead to an excess storage of H2O2, which
further increases the hydroxyl radicals and lipid peroxide that
signal the cell to undergo a programmed cell death. The influenza
virus induces ROS production in host cells that can damage the
virus genome which ROS enhance the pathogenesis ability of
infectious influenza that leads to the thymus-specific elevation of
the mitochondrial superoxide, which interferes with the normal
functioning of T-cells lymphocyte damage in influenza A virus
infections. Zinc-associated vaccine activity mechanism against
viruses is indicated that the anti-viral vaccine activity of released
Zn2+ ions from zinc solutions and ZnO NPs, may be enhanced by Zn2+ ion-induced Zn2+ ions-coordinated adapted immunity, viral
growth regulation, and viral apoptosis and death.
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