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PATHOGENESIS OF RNA VIRUS AND RECENTLY AVAILABLE

THERAPEUTICS IN TREATMENT - A REVIEW

Rishav Kar*1

, Kousik Bhattacharya*2

*1,2Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College Rahara,

Kolkata, India.

ABSTRACT

Viral outbreaks are not new things in the history of human civilization. There are many of the past

documentations of viral pandemics or epidemics that show in most of the cases these are the RNA virus. Rate of

mutation in case of RNA virus is quit high which is the leading cause of its outbreak. This review article will

elaborately contain the detail infection mechanism of RNA virus along with some examples of each group. Not

only that all recently available antiviral drugs are also listed here which are used in treatment of RNA virus

infection. This review work will support the researchers in the respective field by giving compact information

about the current situation that will eventually helps in development of research in this field in future.

Key words: RNA virus, infection mechanism, antiviral drugs.

I. INTRODUCTION

All of the living beings on earth must have three things as the signature of life. These are cellular environment,

genetic materials (DNA or RNA) and energy producing mechanism i.e. metabolism. If a particular matter ticks

all of the three mentioned characters then only we can say that this is a living being. What about virus? They

don‟t have cellular structure, they lack proper energy producing mechanism of their own but they have genetic

material either DNA or RNA. Hence it is not possible to categorize virus in either living category or non-living

category. It is an amazing creation of nature which is partly living and partly non-living. But the more

interesting thing is that these microscopic a cellular particles can hijack both of unicellular bacteria to multi

cellular humans. Virus takeover all the biological activities of the host to multiply its own number and

ultimately comes out from that cell by bursting it. An a cellular particle can rule the cellular organisms!

On the basis of the genetic material present, virus can broadly be classified into two groups i.e. DNA virus and

RNA virus. It is not observed that a virus containing both the DNA and RNA at a single time. Some members of

the both groups are pathogenic and some are non pathogenic, but comparatively RNA virus are more infectious

than DNA virus. There several examples of epidemics are present in the history of human civilization because

of this virus. In all the cases of viral outbreaks proper therapeutics by designing proper antiviral drugs or

vaccines are done. Here in this review the types of RNA viruses, their pathogenesis and available antiviral drugs

in treatment of them along with their mode of action are discussed.

Mode of infection of RNA virus:

RNA viruses are those virus which contains RNA as their genetic material. To infect a host cell a Virion

(i.e.potential enough to produce infection)must undergo replication in the host cell to increase it‟s load in the

host body.after entry in the host body first of all the virus has to cross the plasma membrane of the target cell to

replicate own genome and uses the host cell ribosome to translate proteins.thus new virions released in the body

increasing the infected cell number to uncountable from just one.

Now mode of infection of any virus generally involves the following steps-

Attachment

Penetration

Uncoating

Replication

Assembly

Maturation

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Release

All viruses must have to go through all the above steps, it may lead to incomplete if one or more of the above is

not completed.( Palmiro Poltronieria etal.2015, Jane Flint etal.2015, Jennifer Louten etal.2016)

1. Attachment

A cell interacts with the extracellular world through the plasma mem¬brane made of phospholipid bilayer and

various molecules in it, and it is the location that a virus first makes contact with a target cell. These molecules

work as the receptor for the virus. Here strength conferred by a receptor for a single virus called Affinity but

presence of multiple receptor binding sites on the virion and fluid nature of plasma membrane allow

engagement of multiple receptors so more strength called Avidity.

Probably electrostatic forces acts in initial association but for more, short range forces like hydrophobic is

observed. attachment involves generally Attachment factors(helps to concentrate viral particles on the cell

surface), Receptors, and an additional cell surface molecule i.e. Co-receptor example: HIV uses Heparin Sulfate

Proteoglycan as attachment factor, CD4 as receptor, CCR5/CXCR4 as co receptor. The virus attachment protein

is located in the outermost portion of the virus. Receptors determine the host range and tropism of the

virus.(Jane Flint etal.2015, Jennifer Louten etal.2016, S Payne etal.2017)

2. Penetration

Penetration involves the successful crossing of the plasma membrane by the virus with specific attachment

factor, receptor, and co-receptor binding .penetration is the virus‟s entry into cell through various cellular

processes like Endocytosis, Phagocytosis, Pinocytosis, Membrane fusion, Vesicular trafficking and so on and

energy required is served by the host cell itself.

Phagocytosis, Pinocytosis these are quite non selective where as Receptor mediated endocytosis is a selective

process occurring after interaction between the external receptor and ligand and internalization involves the

clathrin coated pits or caveolin or lipid raft or an independent process and macro pinocytosis. Among the above

stated processes Clathrin mediated endocytosis is used by most viruses as wide range of ligand, fluid, membrane

protein, and lipids are selectively taken into the cell. Whereas enveloped or non enveloped both viruses follows

endosome formation to avoid internal cytoplasmic barriers, “early endosomes,” slightly acidic vesicles (pH of

6.0–6.5) that becomes “late endo¬somes” with more acidity(pH of 5.0–6.0) and then to lysosomes, larger

vesicles full of digestive enzymes and very low pH. Most virus enters into the cytoplasm through late endosome

and some through the lysosomes.( Jane Flint etal.2015, Jennifer Louten etal.2016, S Payne etal.2017)

3. Uncoating

Uncoating of RNA viruses generally releases viral nucleocapsid in the cytoplasm. Hence uncoating means to

release the viral nucleocapsid after the endosome-lysosome transport system. After endocytosis at certain pH

membrane fusion occurs to release viral genetic material in the cell cytoplasm(example:Influenza shows an acid

catalyzed membrane fusion)by a endosomal fusion receptor(example: Ebola virus)(Influenza and Ebola virus

discussed later). As the viral nucleocapsid is released various Cargo proteins perform docking(it is a natural

cellular process)at the nucleo pore forming complexes to transport the genetic material in the nucleus for

replication of other necessary steps to be followed. ( Jane Flint etal.2015, Jennifer Louten etal.2016, S Payne

etal.2017)

4. Replication

Now, all the steps above describes that the “Hijack” of cellular mechanism has already began. A virion after

successfully performing all the steps goes for replication to make more progeny viruses to infect other cells

previously said. Replication involves the generation of various copies of the genome of a virion and various

structural and functional proteins are translated for progeny virion. Generally for RNA virus replication occurs

at the cytoplasm but exceptional viruses replicate their gene in the nucleus (example: Influenza virus and Retro

virus). The replication strategy is generally dependent upon the type of nucleic acid genome the virus have.(

Jane Flint etal.2015, Jennifer Louten etal.2016, S Payne etal.2017,Yizhi Jane Tao etal.2010). Previously it was

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said that RNA virus has RNA as genetic material. According to genetic material type now RNA viruses are

divided into following types-

A. Double Stranded RNA Virus

B. Single Stranded RNA Virus

C. Segmented virus

D. Retro virus

All of the above are described below:

A. Double Stranded RNA Virus

Double Stranded RNA Viruses are generally all no enveloped and produce icosahedral capsid. They generally

have a segmented genome and so far reported that two families of them are responsible to cause human disease

they are-

a. Reoviridae

b. Picobirnaviridae

Reoviridae family has Rotavirus, which is known to be a leading cause of severe, dehydrating gastroenteritis in

children <5 years of age.

Picobirna viruses are another family that infect humans, but they have two genome segments that together are

around 4.2 kb in length and are believed to be associated with severe gastroenteritis disease among people of

developing countries and also in children worldwide. Yet in some cases reported to be a cause of respiratory

disease. (Massimo LIBONATI etal.1980, Jane Flint etal.2015, Jennifer Louten etal.2016,Susanne Modrow

etal.2013).

Example of Double Stranded RNA Viruses is Rotavirus

Rotavirus:

The RVA genome is approximately 18,500 bp in size with 11 segments of Double Stranded RNAs which

encode 6 structural and 6 non-structural proteins. They are like-a.viral protein1(VP1), b.VP2, c.VP3, d.VP4,

e.VP6,f.VP7-these all are structural and for non- structural –a.VP5,b.NSP2,c. NSP3,d. NSP4,e. NSP5,f. NSP6.

VP2 can be cleaved by trypsin or cellular protease into VP5* and VP8*(. Goff etal.2013, Ulrich Desselberger

etal.2014, Carlos F. Arias etal.2015)

Attachment:

For attachment of the infectious Retro virus particle, the Triple layerd particle, the virion consisted of, interacts

by its VP4spikes with cellular receptors (attachment receptors). The receptors contain sialic acid (SA) in

terminal or sub-terminal positions. As for co-receptor various cell surface molecules can participate but all co-

receptors are associated with lipid rafts, i.e. detergent-resistant lipids close to the cellular plasma membrane.VP4

and VP7 for remaining at the outer surface contribute attachment.( Ulrich Desselberger etal.2014, , Carlos F.

Arias etal.2015)

Entry:

After binding, the cell penetration mechanism of Rotavirus remains unclear. The presence of cholesterol and

GTPase dynamin on cell membranes are required for RV entry. ( Ulrich Desselberger etal.2014, Carlos F. Arias

etal.2015)

RV plus strand RNA synthesis:

RV particles possess their own transcription complexes (TCs), consisting of VP1, the viral RNA-dependent

RNA polymerase(RdRp), and VP3 and the viral capping enzyme. The TCs are localized at the inner surface of

the VP2 (core) layer .Each TC is made with a viral RNA segment. Rotavirus Double layer particles in cytoplasm

produce capped, non-polyadenylated, (+) ssRNA transcripts (from the negative strand of the genomic RNA) . (

Ulrich Desselberger etal.2014)

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Viroplasm formation:

Rotavirus proteins and RNAs interact specifically in cytoplasmic inclusion bodies that is defined as

„viroplasms‟. For the formation of viroplasm, the presence of two of the RV non-structural proteins i.e.NSP2

and NSP5, is essential and sufficient. ( Ulrich Desselberger etal.2014, J.T.Patton etal.2006, Lynn S. Silvestri

etal.2014)

RNA packaging in new virus and (-) strand RNA synthesis:

For the persistence length of the naked dsRNA it is unpackageable in the virion. Whereas the 11different (+)

ssRNA segments are reassorted, interact with viral coreproteins to get perfectly packaged and replicated.

According to the assumption that primary replication complexes of VP1/VP3/ssRNA may interact with a VP2

(most likely involving NSP5 and NSP2) leading to the formation of core particles. Simultaneously, the negative

charge of the RNA has to be neutralized. During replication it was observed that both newly synthesized and

pre-existing (+) strand RNA can act as a template for (-) RNA synthesis. It is still unclear that how the

packaging of the correct set of 11 RNA segments into individual particles is controlled. ( Ulrich Desselberger

etal.2014,)

Virion maturation and release of Rotavirus:

In the maturation process, NSP4 serves as an intercellular receptor by interacting with VP6. Within the Endo-

plasmic reticulum, nascent RV particles are enveloped very quickly, but the envelope is lost when RV particles

are acquired with VP4 and VP7at the outer layer. ( Ulrich Desselberger etal.2014,Sarah M. McDonald

etal.2011)

B. Single Stranded RNA Virus

Single stranded RNA virus contains only one type of RNA as genetic material

a. Viruses with ssRNA genomes that can act directly as mRNA(directly translates protein) are known as

positive-sense RNA viruses (abbre¬viated +ssRNA).

b. Similarly, ssRNA viruses with genomes that are not able to be immediately translated by host ribosomes are

known as negative-sense RNA viruses (abbreviated -ssRNA).

a) (+) ss RNA virus

+ssRNA viruses are more abundant than any other class of viruses infecting a wide range of host species. They

include seven different human viral families, including the disease causing ones in humans like coronaviruses,

flaviviruses, and picornaviruses. Their abundance indicates that +ssRNA viruses have been very successful

evolutionarily. Here the viral genetic material itself acts as basic tool for translation by the host ribosome i.e.

mRNA and have 5′-caps (or proteins that act similarly to a 5′-cap) also often contain poly(A) tail sequences at

the 3′-end. Generally dsRNA virus carries a RNA dependent RNA polymerase but this types encode it in their

genome. ( Jane Flint etal.2015, Jennifer Louten etal.2016, S Payne etal.2017)

A common characteristic of +ssRNA viruses is that their infectious genome encodes a polyprotein, i.e. the

genome is translated by ribosomes into a long chain of amino acids which is cleaved into several smaller

proteins. Here viral genome is needed to create an negative strand i.e. Antigenomic RNA which further used as

primer for +RNA synthesis. .( Jane Flint etal.2015, Jennifer Louten etal.2016, S Payne etal.2017, Alexander A

Khromykh etal.2000).

Coronavirus is taken as an example here.

Coronavirus

Coronaviruses are spherical or pleomorphic, with a diameter of 80–120 nm. Under the electron microscope, the

virion surface is decorated with club-like projections constituted by the trimeric spike (S) glycoprotein. Shorter

projection of Hemaglutinin esterase are seen in some.

The viral envelope is supported by the membrane (M) glycoprotein, which being the most abundant structural

protein remains embedded in the envelope via three transmembrane domains. Along with that, a small

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transmembrane protein known as the envelope (E) protein is also present in a low amount in the envelope.

Finally, the nucleocapsid (N) protein binds to the RNA genome in a beads-on-a-string fashion, forming the

helically symmetric nucleocapsid.

The coronavirus genome is a positive-sensed, nonsegmented, single-stranded RNA genome, with a large size of

27 to 32 kilobases. The genomic RNA is 5‟ capped and 3‟ polyadenylated with multiple open reading frames

(ORFs). The coronavirus replicase is encoded by two large overlapping Open Reading Frames (ORF1a and

ORF1b), that occupy about two-thirds of the genome and is directly translated from the genomic RNA.

Subgenomic RNA translates structural and accessory genes,generated during genome transcription/replication.

Among the 6 known viral strains to infect humans only Severe Acute Respiratory Syndrome coronavirus(SARS-

Cov)and Middle East Respiratory Syndrome Coronavirus(MERS-Cov)are zoonotic and are known to cause

various endemic and pandemic cases worldwide. Example-In November 2002, a viral respiratory disease first

appeared in southern China and quickly spread to other countries, leading to over 8,000 confirmed cases at the

end of the epidemic in June 2003, with amortality rate of - 9.6% (Susan R. Weiss etal.2005, To Sing Fung

etal.2019, Pandurangan Vijayanand etal.2014)

Attachment:

Attachment is facillited by binding of S protein to the cell surface receptors. It contains two parts : S1(bulb) that

participates in receptor binding and S2(stalk) that participates in membrane fusion. Some has adopted cell

surface enzymes as receptor as angiotensin converting enzyme 2 (ACE2) for SARS-CoV, and dipeptidyl

peptidase 4 (DPP4) for MERS-Cov. Host factors are also known to restrict virus entry such as: interferon

inducible transmembrane proteins (IFITMs) exhibited broad-spectrum antiviral functions against various RNA

viruses similarly for SARS-COV and MERS-COV.( To Sing Fung etal.2019, Susan R. Weiss

etal.2005,M.Alejandra Tortorici etal.2019,Anthony R.Fehr etal.2015)

Entry:

Entry involves the cleavage of S protein parts S1 and S2 by various cellular cystein protease cathepsin L as

SARS-Cov requires sequential cleavage by the endosomal cysteine protease. cathepsin L and another trypsin-

like serine protease and after fusion the nucleocapsid is released in the cytoplasm.( To Sing Fung etal.2019,

Susan R. Weiss etal.2005, Anthony R.Fehr etal.2015)

Replication:

Using the genomic RNA as a template, the coronavirus replicase synthesizes full-length negative sense

antigenome, which further serves as a template for the synthesis of new genomic RNA. Generally genome

replication/transcription is mediated by the viral replicase and confines in the Replication Transcription

Complex, also the involvement of various host factors has been implicated. Glycogen synthase kinase3

phosphorylate the nucleocapsid protein of SARS-Cov and facilitate viral replication also Heterogenous Nuclear

Ribonucleoprotein A1, a rna binding protein regulates viral rna synthesis. Host RNA-binding proteins could also

bind directly to untranslated regions (UTRs) of the coronavirus genome to modulate replication.

Transmembrane structural proteins and some membrane-associated accessory proteins are translated in the endo

plasmic reticulum, whereas the N protein is translated by cytosolic free ribosomes.( To Sing Fung etal.2019,

Anthony R.Fehr etal.2015, Susan R. Weiss etal.2005, D. A. Brian etal.2005)

Assembly and release:

Assembly of particles occur at ER-golgi intermediate compartment by M protein , E protein also helps in

assembly and induction of membrane curvature. Finally, coronavirus particles budded into ER-golgi

intermediate compartment are transported in smooth-wall vesicles and trafficked via the secretory pathway for

release by exocytosis.( To Sing Fung etal.2019, Anthony R.Fehr etal.2015)

b) (-)ss RNA

Negative sense strand RNA genome containing rna viruses can‟t directly access cellular ribosomes for

translation process so like DNA viruses they have to carry on their own RNA dependent RNA polymerase in

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their virion coat. These rna viruses may be segmented or not. Some of the most infectious strains for human of

this type includes Ebola virus, Marburg virus, measles virus, mumps virus, rabies virus, and influenza virus.(

Jane Flint etal.2015, Jennifer Louten etal.2016, S Payne etal.2017)

As for example here Ebola virus is taken which has a very high mortality rate observed in certain outbreaks.

Ebola virus

Ebola virus belongs to Filoviridae family and known as emerging zoonotic pathogens causing acute

hemorrhagic fever with a high case-fatality rate in humans (up to 90%). Recent outbreaks include Democratic

Republic of Congo from 2017 to till the date and West Africa from 2014-2016 rendering a huge number of

people to death.

All known EBOV strains consist of four different species: Zaire ebolavirus (ZEBOV), Sudan ebolavirus

(SEBOV), Côte d‟Ivoire ebolavirus (CIEBOV) and Reston ebolavirus (REBOV) and the newly discovered

Bundibugyo ebolavirus (BEBOV) has been proposed as the fifth species. The species vary in their apparent

pathogenicity in humans; ZEBOV is the most pathogenic (up to 90% case fatality rate). Ebola virus includes

high levels of inflammatory cytokines, coagulation abnormalities and fluid distribution problems. These

processes are observed as hemorrhage and vascular leakage; ultimately leading to multiple organ failure and

shock.

Transmission of virus involves direct contact with body fluids containing virus (vomitus, sweat, stool, urine,

tears, breast milk, saliva and respiratory secretions) of an infected patient during the acute stage of disease.

(Dong-Shan Yu etal.2017, Saeed Reza Jamali Moghadam etal.2015, L Falasca etal.2015, Athena P. Kourtis

etal.2015)

Structure:

Filoviruses are enveloped particles with a non-segmented, single stranded,

negative-sense RNA genome, approximately 19 kb in size and so similar for EBOLA also. The virus shape is

very variable with long tubes and many turns and branches. EBOV(Ebola virus) genomes encode seven

structural proteins, and also encodes two nonstructural soluble glycoproteins (GP): soluble GP and small soluble

GP.

The large virus structure is composed of three compartments 1.the nucleocapsid, 2.the matrix space and 3.the

envelope. The seven genes encodes the nucleoprotein (NP), the viral proteins VP24,VP30,VP35,VP40, L

(polymerase) and the glycoprotein (GP). The surface GP is coded by the GP gene which has important roles in

virus infection and pathogenesis, and its expression is tightly regulated during virus replication. The NP embeds

the genetic material, forming complex with proteins VP30 and VP35 that is involved in synthesizing virus

RNAs also Separate genes code for proteins VP40 and VP24 localized in virus matrix space.( Dong-Shan Yu

etal.2017, Saeed Reza Jamali Moghadam etal.2015, JEffrewy E Lee etal.2009, Rebecca Reece etal.2016)

Attachment and entry:

Different attachment mechanism is adapted by Ebola virus to infect various cells except the lymphocyte cells

and can enter the target cells by using different uptake mechanisms including lipid raft, receptor-mediated

endocytosis and macropinocytosis. The size of the virus takes it aginst the clathin mediated or caveolin mediated

endocytosis so the cholesterol-enriched lipid raft microdomains seem to be very important for EBOV entry. In

fact, it has been shown that entry requires functional rafts by viral glycol protein spike attached with an

unknown receptor.

The virus follows membrane fusion at endosome through a specific fusion receptor at endosome membrane

called Niemann-Pick C1which is known to participate in cholesterol transport. Virus bind to the above with

GP,cysteine protease cleaves the GP to remove heavily glycosylated mucin and glycan cap. Analyses of human

samples obtained from various patients or from experimentally infected animal models indicated that

monocytes/macrophages, DCs, fibroblasts, hepatocytes, adrenal cells and epithelial cells are productively

infected by this virus.(Jeffery E Lee etal.2009, Sven Moller-Tank etal. 2015, Bethany A. Rhein etal.2015)

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Replication, assembly and release:

The seven genes encodes the nucleoprotein (NP), the viral proteins VP24,VP30,VP35,VP40, L (polymerase),

soluble GP, Δ-peptide, ssGP and the glycoprotein (GP). The surface GP is coded by the GP gene which is

expressed in two forms (GP1 and GP2). It has been recently demonstrated that the GP1 and GP2 levels regulates

the expression of the virus production and release. The NP embeds the genetic material, forming complex with

proteins VP30 and VP35 that is involved in synthesizing virus RNAs also separate genes code for proteins VP40

and VP24 localized in virus matrix space. Whereas, Filoviruses released from infected cells contain raft-

associated molecules, suggesting that viral exit occurs at the rafts and on this idea the plasma membrane raft

micro domains as possibly to represent the gateway for the entry and exit of the virus.

GP-tetherin(Tetherin is an IFN-a-induced, cell-surface protein-based tether which can induces virion retention

on the cell membrance) interaction, VP24-induced correct assembly, NP-related nucleocapsid transport and the

incorporation into virions, and VP40- inner leaflet association these are some well clarified and known

mechanism of viral assembly and budding.(Ziying Han etal. 2003,Takeshi Noda etal.2006,Dong Shan Yu

etal.2017)

C. Segmented virus

This group of virus includes generally virus with negative stranded RNA as their genome but in a segmented

orientation. Best studied example is Influenza virus.(A.J.Shaktin wtal.1971, Jane Flint etal.2015, Jennifer

Louten etal.2016)

Influenza virus

Influenza virus belongs to the family of Orthomyxoviridae. The three influenza virus types, A, B, and C based

on the immunologically distinct nucleoprotein and matrix protein antigens. Influenza B and C viruses are

associated with low-level sporadic disease and are never causes of pandemic influenza. influenza A is

responsible for most seasonal influenza and all known pandemics. Mode of transmission involves generally 3-

Droplet transmission

Airborne transmission

Contact transmission

The incubation period generally appears to be 7 days or less, and in many cases this period is 2 to 5 days. Initial

symptoms of H5N1 influenza may include fever (typically a temperature of more than 38°C), headache,

malaise, myalgia, sore throat, cough, and rhinitis with lower respiratory tract symptoms, shortness of breath and

radiological evidence of pneumonia.(Nicole M.Bouvier etal.2008, Gemechu Regea etal.2017, Raphael Böhm

etal.2014, Jane Flint etal.2015, L.E.Davis etal.2014)

Structure:

80-120nm in diameter, spherical and enveloped. On the surface of influenza virus reside two major proteins;

Haemagglutinin (HA) and Neuraminidase (NA) resides. Sixteen subtypes of HA (H1 to H16) and nine subtypes

of NA (N1 to N9) are recognized in aquatic birds. Death mostly occurs as a consequence of primary viral

pneumonia or of secondary respiratory bacterial infections, especially in patients with underlying pulmonary or

cardiopulmonary diseases. The matrix protein M1 is positioned as a highly organized helical structure under the

lipid containing envelope and gives the envelope strength and rigidity. The three viral surface glycoproteins

including the M2 protein that participate in ion channel activity and the viral spike proteins NA and HA stand

out from the envelope and recognized as the main pathogenicity factors.( Raphael Böhm etal.2014, Jeffery K.

Taubenberger etal.2008, Jane Flint etal.2015, Julie L. McAuley 2019)

Attachment:

The ligand of Influenza virus is trimer Haemagglutinin Glycoprotein Spike Protein. Each monomer is composed

of 2 peptide subunits called HA1 and HA2.

The globular head part of HA1 containing a conserved region binds to the N-acetyl Neuraminic acid(Sialic

acid)cellular receptor. Sailic acid residues are available in many cells including RBCs. Haemaglutination or

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clumping of RBCs is caused by viral haemaglutinin protein.( Jane Flint etal.2015,Satoshi Fukuyama etal.2011,

Gemechu Regeaetal.2017, Jennifer A. Thorley etal.2010 )

Entry and uncoating:

Entry of the virion is facilitated by Receptor mediated endocytosis process. Next importance comes to uncoating

by membrane fusion. From structural analysis it is observed that until the M1-viral Ribonucleo Protein

interactions are disrupted, vRNPs might not be released in the cytoplasm. Here the M2 protein starts activity.

Activation of M2 channel by the low pH of the endosome leads to conformational changes in the M1 protein

and M1-vRNP interactions disrupted.( Jane Flint etal.2015)

The virus-receptor complex after endocytosis import of H+ ions into the endosome acidifies the interior. Upon

acidification, the viral HA undergoes a conformational rearrangement producing a fusogenic protein. The loop

region of native HA turns into a coiled structure, moving the fusion peptides to the top of the molecule near the

cell membrane. The long coiled coil bends, or hairpins, and brings the fusion peptides and the transmembrane

domains together. This movement moves the cell and viral membranes close together for fusion. To allow

release of vRNP into the cytoplasm, the H+ ions in the acidic endosome are pumped into the particle interior by

the M2 ion channel. As a result, vRNP is ready to dissociate from M1 after fusion of the viral and endosomal

membranes and thus released in cytoplasm.( Jane Flint etal.2015, Dan Dou etal.2018, Xiangjie Sun etal. 2006 )

Transport to the nucleus:

As discussed earlier about this exception here comes some description that replication of segmented genome of

Influenza occurs at the nucleus. Transportation involves the classical Nuclear Import Pathway, specially

occurring for proteins in general containing the NLS or Nuclear Localization Signal. As the vRNPs separate

from M1 and released into cytosol presence of NLS in NP protein of the virus i.e. a component of vRNPs.( Jane

Flint etal.2015, Dan Dou etal.2018, Raphael Böhm etal.2014, Gemechu Regea etal.2017)

Replication:

Each of the virus genome segments replicates independently. The positive sense RNA which is generated from

the genome template is probably by de novo synthesis. The newly-synthesized positive sense antigenome RNAs

in nucleocapsid complexes, are used as templates for the production of negative sense ssRNAs.

Virion contains proteins that can transcribe mRNA but these enzymes cannot cap and methylate the viral

mRNAs so the virus must acquire it‟s cap from host cell. Viral p protein cleave short sequences from 5‟ end of

the host mRNAs which are already capped and methylated and as primers for the viral mRNA synthesis. (Jane

Flint etal.2015, Dan Dou etal.2018, Raphael Böhm etal.2014, Gemechu Regea etal.2017)

Assemble and release:

The progeny are assembled with H and N proteins inserted at the inner region of the host plasma membrane.

After assembly the progeny viruses are released from the cell. In the cytoplasm the vRNPs are trafficked to the

plasma membrane by Rab11.

But when several strains infect a cell or host a chance of Reassortment relies where more than two strain‟s

genetic materials can form new viral strain for Epidemic and Pandemic diseases in human society.( Jane Flint

etal.2015, Dan Dou etal.2018, Raphael Böhm etal.2014)

D. Retrovirus

Retro viruses are those viruses which transcribe DNA from their genetic material i.e. a RNA it is called Reverse

Transcription and enzyme associated with the phenomenon called Reverse transcriptase i.e. a RNA dependent

DNA polymerase within the virion. Yet reverse transcriptase can also act as a DNA dependent DNA polymerase

and also as RNase H.

One of the best known example of it includes HIV(Human Immunodeficiency Virus). Infected ones become

immune compromised hence death occurs by even mild infections, overcame by normal people. Genomic

organization of Retrovirus involves two identical linear ssRNA molecule of (+)strand and genes are –

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Gag-encodes viral structural proteins

Pol-encodes reverse transcriptase and DNA endonuclease

Env-encodes envelop protein

Some Retro virus contains a 4th gene considered to be involved in cancer and cellular transformation(Example-

Src gene of Rous sarcoma virus)(coffin JM etal. 1997, Jane Flint etal.2015, Wang-Shick Ryu etal.2017, J Karn

etal.2013, . Goff etal.2013)

Human immune-deficiency virus(HIV-1)

Attachment and entry:

The cell receptor for HIV1 is CD4 protein, a 55-kDa rod like molecule that belongs to the Ig super family and

has four Ig-like domains. An additional cellular protein is also required. Generally Heparan Sulfate

Proteoglycan acts as attachment factor then CD4 as receptor and the last one is CXCR4 for strains that infect T

cell preferentially, whereas CCR5 for strains that infect macrophages. Attachment via CD4 creates a high-

affinity binding site on Surface Envelop protein for CCR5. This above mentioned high affinity may induce

conformational changes in Trans membrane protein to expose the fusion peptide, placing it near the cell

membrane.

Human immunodeficiency virus type 1 Trans membrane mediates envelope fusion with the cell membrane.

Finally the nucleocapsid enters the cell cytoplasm where uncoating is completed.( Ahmed Ali Hussein etal.2017,

Jane Flint etal.2015, Shokouh Makvandi-Nejad etal.2015, G.M.Shaw etal.2012)

Replication:

After entry viral reverse transcriptase reverse transcribe viral mRNA to DNA with a very poor Proof reading

activity. Again it is transcribed to a double stranded DNA using host cell nucleotides in the cytoplasm. Then

another enzyme called integrase takes the dsDNA through the nucleo pore and integrate it into the cellular DNA

now it is called Provirus. Which further is transcribd by RNA polymerase. Integration to DNA is the key step

from where host is inherited with life long infection. Then those mRNAs are translated by host ribosomes at

Rough endoplasmic reticulum from where envelop protein generates. Simultaneously other mRNA translate

multi chain proteins.(Prof.Dr.Lutz Gurtler etal. 2015, Jane Flint etal.2015,)

Assembly and Release:

All the encoded proteins are organized at cell plasma membrane. With two viral mRNAs of (+) strands the

membrane forms a vesicle in extra cellular fluid, yet it is not a complete virion until the multi chain proteins are

cleaved by certain protease forming complete virion released in a huge number from a single infected cell.

Hence cellular mechanism is hijacked and used as a factory of growth by the virion.( Jane Flint etal.2015,

Shokouh Makvandi-Nejad etal.2015, Wesley I.Sundquist etal.2012)

Drugs in treatment of RNA viruses:

RNA virus uses their genomic RNA molecule in each key step from initial adsorption to final cell bursting.

Most RNA elements involved in viral replication function as the basic stem–loop units, which are highly

conserved and predominantly reside in the 5‟ and 3‟ non-coding regions of the viral genome. This is very much

conserved organization and mutation in just one nucleotide base can alter the total system by either gaining any

function or by losing any function. And in other hand these viruses has the ability which lack polymerases with

proofreading function, to undergo mutation is notoriously high. Thereby careful selection of an appropriately

conserved RNA target is needed to reduce the occurrence of resistance mutation against a selected antiviral.

Available therapeutics in treatment of RNA viruses till date are listed below-

Name Uses and Mode of Action

Adapromine

Antiviral drug of adamantine group used in treatment of influenza. Have

similar activity with rimantadine and also have broad spectrum of activity like

anti depressant.

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Amantadine This is also used in treatment of RNA viruses. It blocks M2 proton channel

thereby preventing viral shedding. It is also used in Parkinson‟s disease.

Baloxavir marboxil

Baloxavir marboxil (BXM) was developed as a prodrug strategy, with its

metabolism releasing the active agent, baloxavir acid (BXA). BXA then

functions as enzyme inhibitor, targeting the influenza virus' cap-

dependent endonuclease activity, used in "cap snatching" by

the virus' polymerase complex, a process essential to its life-cycle.

DRACO

It has broad spectrum antiviral activity used in treatment of Dengue virus,

Arena virus, Influenza, Rhino virus etc. It was reported to induce

rapid apoptosis selectively in virus-infected mammalian cells, while leaving

uninfected cells unharmed.

Favipiravir

It is a pyrazinecarboxamide derivative. It shows activity against influenza

viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus . The

mechanism of its actions is thought to be related to the selective inhibition of

viral RNA-dependent RNA polymerase. avipiravir is a prodrug that is

metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate

(favipiravir-RTP), available in both oral and intravenous formulations.

FGI-106

It is specially used in treatment of enveloped RNA viruses, like Flavi virus,

Buya virus, Filo virus etc. It acts as an inhibitor which blocks viral entry into

host cells.

Galidesivir

It is an adenosine analoge antiviral drug. Initially it is used in treatment of

HCV but it shows a broad spectrum antiviral activities against Corona virus,

Filo virus, Phlebo virus, Arena virus etc.

IDX-1884

IDX-184 is an antiviral drug which was developed as a treatment for hepatitis

C, acting as a NS5B RNA polymerase inhibitor. It also has useful activity

against Zika virus and Corona virus.

Lumicitabine It is an inhibitor of RNA polymerase enzyme. It principally used in treatment

of RSV and Human metapneumo virus.

Mericitabine Mericitabine is an antiviral drug, a deoxycytidine analog. It was developed as a

treatment for hepatitis C, acting as a NS5B RNA polymerase inhibitor.

MK-608 It is originally developed to treat HCV. It is actually an adenosine analog that

shows large scale activity against dengue, Zika virus and tick borne viruses.

Mozenavir

This antiviral drug developed to treat HIV. It shows the protease inhibitor

activity of the HIV, moreover it has very high affinity to bind to protease and

inhibit it.

NITD008

It is a potential antiviral drug against Flavi virus, but it also has uses against

dengue virus, West Nile virus, yellow fever virus, Powassan virus, hepatitis C

virus, Kyasanur Forest disease virus, Omsk hemorrhagic fever virus, and Zika

virus. It is an adenosine analog in nature.

Pimodivir It is a potential drug against influenza. It acts as an inhibitor of influenza virus

polymerase basic protein 2.

Pleconaril

This antiviral drug is used for prevention of asthma exacerbations and common

cold symptoms in patients exposed to Picornavirus respiratory infections.

Prevents the virus from exposing its RNA, and in rhinoviruses Pleconaril

prevents the virus from attaching itself to the host cell.

Presatovir This is an antiviral drug which was developed as a treatment for respiratory

syncytial virus (RSV). It acts as a fusion inhibitor.

Remidesivir

It is a novel antiviral drug in the class of nucleotide analogs. Remdesivir is

an adenosine analogue, which incorporates into nascent viral RNA chains and

causes their pre-mature termination. It also has uses in treatment of COVID19.

Ribavirin This is an antiviral medication used to treat RSV infection, hepatitis C. It‟s

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carboxamide group can make the native nucleoside drug resemble adenosine or

guanosine, depending on its rotation. For this reason, when ribavirin is

incorporated into RNA, as a base analog of either adenine or guanine, it pairs

equally well with either uracil or cytosine, inducing mutations in RNA-

dependent replication in RNA viruses. Such hypermutation can be lethal to

RNA viruses.

Rintatolimod

The mechanism of rintatolimod in relation to CFS is not certain, but is thought

to include the RNaseL enzyme. This enzyme degrades pathogenic RNA, both

viral and cellular. Degradation of RNA prevents viral and cell replication and

destruction of all RNA within a virus or cell is the last step before apoptosis or

death. Accumulation of an inactive form of RNaseL may be associated with

CFS.

Taribavirin

It is a prodrug of ribavirin. Taribavirin is as active against influenza as

ribavirin. Taribavirin has better liver-targeting than ribavirin and has a shorter

life in the body due to less penetration and storage in red blood cells.

Umifenovir

Umifenovir inhibits membrane fusion. Umifenovir prevents contact between

the virus and target host cells. Fusion between the viral envelope and the cell

membrane of the target cell is inhibited. This prevents viral entry to the target

cell, and therefore protects it from infection. It mainly used in treatment of

Influenza virus.

Uprifosbuvir This antiviral drug developed for the treatment of Hepatitis C. It is

a nucleotide analogue which acts as an NS5B RNA polymerase inhibitor.

Valopicitabine

It is an antiviral drug which was developed as a treatment for hepatitis C. It

acts as a RNA-dependent RNA polymerase inhibitor. It is a pro drug which is

converted inside the body to the active form, 2'-C-methylcytidine triphosphate.

Ziresovir This antiviral drug was developed as a treatment for respiratory syncytial virus

(RS). It acts as a fusion inhibitor.

II. CONCLUSION

Recently the whole world is suffering to corona virus pandemic which is also a RNA virus itself. Not only

corona virus, past viral outbreaks which already documented are RNA virus in most cases. So it‟s pretty clear

that we have to be ready for such outbreaks in future also. And we can also predict that if viral epidemics will

happen in future again most probably it will be RNA virus. For this the detail infection mechanism of the virus

and current status of antiviral drugs used have to be known. This review work contains all these information in a

very compact way so that will be helpful to develop the research further in this field.

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