Virus Classification, Structure & Replication

Youhua Xie(谢幼华)Youhua Xie(谢幼华)

MOH&MOE Key Lab of Medical Molecular VirologySh h i M di l C ll F d U i itShanghai Medical College, Fudan University

复旦大学上海医学院

分子病毒学教育部/卫生部重点实验室分子病毒学教育部/卫生部重点实验室

yhxie@fudan.edu.cn

The Nature of Viruses

Viruses are small infectious agents (diameter 20‐300 nm) 

Infectious agents smaller than viruses: viroids, prionsGi t i Mi i i (400Giant virus: Mimivirus (400 nm, genome size 1.2 Mb), Pandoravirus (1 um, genome size 1.9-2.5 Mb)

The Nature of Viruses

Viruses contain one kind of nucleic acid (DNA or RNA genome)Viruses contain one kind of nucleic acid (DNA or RNA genome) inside a protein shell (capsid), which may be surrounded by a lipid bilayer membrane (envelope). The resulting complete virus particle y ( p ) g p pis called a virion

All Cellular Lives Survive in a Sea of Viruses

Viruses are major players in the ecosystem infecting everyViruses are major players in the ecosystem, infecting every cellular life

Animals: animal virusesPlants: plant virusesArchaea: archae virusesFungi: mycoviruses （真菌病毒）

Bacteria: bacteriophages (噬菌体）

……Viruses constitute a substantial amount of biomass on the earth ( th 1030 b t i h ti l l i t th(eg. there are 1030 bacteriophage particles alone in waters on the earth)

1 phage weighs about 1 femtogram (10-15 gram )1 phage weighs about 1 femtogram (10 gram )1030 phages weigh about = 10-15 x 1030 = 1015 gram = 1012 kilogram = 109 tons

Viruses Are Obligate Cellular Parasites

Viruses multiplicate (replicate) inside host cellsVi tili ll l hi i f li tiViruses utilize cellular machineries for replication

synthesis of proteinssynthesis of membranessynthesis of amino acid, carbohydrates and lipidsgeneratation of energy

Selected Milestones in Virology

Discovery Year Scientist Nobel iprize

Smallpox vaccine 1798 Edward JennerRabies vaccine 1885 Louis PasteurRabies vaccine 1885 Louis PasteurViruses are filtrable

Tobacco mosaic virus 18921898

Dimitrii IvanovskiMartinus Beijerinck1898 Martinus Beijerinck

Rous Sarcoma virus 1911 Peyton Rous 1966Bacteriophages and the 1915 Frederick Twortplaque assay 1917 Felix d’HerelleCrystallization of tobacco mosaic virus

1935 Wendell Stanley and John Northrup 1946mosaic virusBacteriophage genes are DNA

1952 Alfred Hershey and Martha Chase 1969

Di f i f 1957 Ali k I d J Li dDiscovery of interferons 1957 Alick Isaacs and Jean Lindenmann

Selected Milestones in Virology

Discovery Year Scientists Nobel Discovery Year Scientists Nobel prize

Polio vaccines 19551960

Jonas SalkAlbert Sabin1960 Albert Sabin

Reverse transcriptase of retroviruses

1971 Howard Temin and David Baltimore 1975

Virus vectors and gentic engineering

1970s Paul Berg 1980

Cellular oncogene in a 1976 Michael Bishop and Harold Varmus 1989gretrovirus

p

RNA splicing in adenovirus 1977 Phillip Sharp and Richard Roberts 1993Di f H 1983 B é Si i F & M i L 2008Discovery of HumanImmunodeficiency Virus

1983 Barré-Sinoussi F. & Montagnier L. 2008

HBV vaccine (recombinant) 1986HPV vaccine (recombinant) 2006

Virus Classification

http://www.ictvonline.org/

“a virus species is a polythetic class of viruses that constitute a replicating lineage and occupy a particular ecological niche”.

A “polythetic class” is one whose members have several i i l h h h d il llproperties in common, although they do not necessarily all

share a single common defining property. In other words, th b f i i d fi d ll ti l bthe members of a virus species are defined collectively by a consensus group of properties.

Common Properties for Virus Classification

Virion morphology

Nature of genome in virionNature of genome in virion

Presence or absence of lipid membrane (envelope)(envelope)

Genome organization and replication

Antigenic properties

Biological propertiesBiological properties

Current ICTV Virus Classification

The most recent report: "Virus Taxonomy: IXth Report of p y pthe International Committee on Taxonomy of Viruses", 2012

目 Orders (-virale): 7

科 Families (-viridae): 96科 Families (-viridae): 96

亚科 Subfamilies (-virinae): 22

属 Genera (-virus): 420

种 Species: 2618种 Species: 2618

Current ICTV Virus Classification

Order Nidovirale

Family Coronaviridae

Subfamily C i iSubfamily Coronavirinae

Genus Betacoronavirus

SpeciesSevere AcuteRespiratory

Nature Review Microbiology 2003

Species RespiratorySyndrom Virus

Baltimore Classification of Viruses

II

ssDNA

II

dsDNA dsDNA-RT(+)ssRNA-RT ssDNA

IVI VII

(+)IIIIV

dsRNA(+) ssRNA mRNA

(-) ssRNA

(-) ssRNA

V

Vertebrate DNA Viruses

Diagram of the vertebrate DNA virusesPrescott-Harley-Klein: Microbiology 5ed

DNA Viruses That Are Pathogens of Human Diseases

Virus Family Genome Virus Diseases

Parvoviridae ss Parvovirus B19 fifth disease, aplastic crisis

Polyomaviridae ds JC virus progressive multifocal leukoencephalopathy

BK virus BK nephropathy in renal transplant patients

Merkel cell virus Merkel cell skin carcinoma

Papillomaviridae ds Some human papillomavirus (eg. Type 16, 18)

cervical cancer, penile cancer and oral cancers( g yp )

Adenoviridae ds Adenoviruses (>50 types) acute respiratory diseases, conjunctivitis, gastroenteritis (type 40 & 41)

Poxviridae ds Smallpox virus (variola), Vaccinia virus, Molluscum contagiosum virus (MCV),

Skin lesions (smallpox, vaccinia, molluscum contagiosum)

etc.

DNA Viruses That Are Pathogens of Human Diseases

Virus Family Genome Virus Diseases

Herpesviridae ds Herpes simplex virus 1 & 2 Oral and genital lesions

Varicella-zoster virus Chickenpox, shinglesVaricella zoster virus Chickenpox, shingles

Epstein-Barr virus Infectious mononucleosis, associated with human neoplasms (Burkitt’s lymphoma,(Burkitt s lymphoma,Nasopharyngeal carcinoma)

Cytomegalovirus can be life-threatening for the immunocompromisedp

Human herpesvirus type 6 & 7

Roseola infantuma (children)

Kaposi sarcoma-associated Kaposi sarcoma primary effusionKaposi sarcoma-associated virus

Kaposi sarcoma, primary effusion lymphoma, some types of multicentric Castleman's disease

Hepadnaviridae ds-RT Hepatitis B virus acute and chronic hepatitis B,Hepadnaviridae ds RT Hepatitis B virus acute and chronic hepatitis B, associated with hepatocellular carcinoma

Vertebrate RNA Viruses

Diagram of the vertebrate virusesPrescott-Harley-Klein: Microbiology 5ed

RNA Viruses That Are Pathogens of Human Diseases

Virus Family Genome Virus Diseases

Picornaviridae + ss Polioviruses poliomyelitis

Coxsackieviruses, Herpangina, Hand, foot and mouth Echoviruses & other enteroviruses

disease, Neurological disease, Heart and muscle disease

Rhinoviruses Common cold

Hepatitis A virus Hepatitis A

Astroviridae + ss Astroviruses Gastroenteritis

C li i i id N i G i iCaliciviridae + ss Norovirus Gastroenteritis

Togaviridae + ss Rubella virus Rubella

Alphaviruses (Ross River, fever, headache, maculopapular skinAlphaviruses (Ross River, Eastern, Venezuelan andWestern equine encephalitis viruses, chikungunya virus)

fever, headache, maculopapular skin rash, arthralgia, myalgia and sometimes encephalitis

RNA Viruses That Are Pathogens of Human Diseases

Virus Family Genome Virus Diseases

Flaviviridae + ss Yellow fever virus Yellow fever

Dengue virus Dengue fever

Japanese encephalitis virus Japanese encephalitis

Hpetitis C virus Hepatitis C

Coronaviridae + ss Human coronaviruses Common coldsCoronaviridae + ss Human coronaviruses Common colds

SARS-CoV Severe acute respiratory syndrome(SARS)

P i id P i fl i P i flParamyxoviridae - ss Parainfluenza viruses typesI–IV

Parainfluenza

Measles virus Measles, acute measles encephalitis

Mumps virus Mumps

Respiratory syncytial virus Common cause of bronchiolitis in infants, may be severe and , ypotentially fatal in babies with underlying cardiac, respiratory or immunodeficiency disease

RNA Viruses That Are Pathogens of Human Diseases

Virus Family Genome Virus Diseases

Orthomyxoviridae - ss, seg. Influenza virus A, B IAV is generally responsible for pandemics and epidemics; IBV often causes smaller or localized andcauses smaller or localized and milder outbreaks

Bunyaviridae - ss Hantaviruses Haemorrhagic fever with renal syndrome, HFRSy ,

Rhabdoviridae - ss Rabies virus Rabies

Filoviridae - ss Marburg virus &Ebola virus

Marburg virus disease andEbola virus disease (severeEbola virus Ebola virus disease (severe, haemorrhagic, febrile illnesses)

Reoviridae ds, seg. Rotavirus the commonest cause of childhood diarrhoeadiarrhoea

Retroviridae + ss -RT HIV-1 AIDS

HTLV-1 Adult T-cell leukaemia/lymphomai l i iTropical spastic paraparesis

Human Viral Infections & Diseases

Virus Structures

Viruses display a wide diversity of shapes and sizes

Viral capsid is made from proteins encoded by the viralViral capsid is made from proteins encoded by the viral genome (capsid porteins or core proteins)

Viral capsid protein subunits (capsomeres) selfViral capsid protein subunits (capsomeres) self-assemble to form a capsid, in general requiring the presence of the virus genome (together called p g ( gnucleocapsid)

Viral capsid shape serves as the basis forViral capsid shape serves as the basis for morphological distinction

Virus Structures

Helical capsidHelical capsid

Composed of a single type of capsomer stacked around a central axis to form a helical structure, which may have a central cavity

This arrangement results in rod-shaped or filamentous virions

Virus Structures

Icosahedral capsidIcosahedral capsid

The optimum way of forming a closed shell from identicala closed shell from identical sub-units

The minimum number of identical capsomers required is twelve, each composed of five identicalcomposed of five identical sub-units

Virus Structures

Complex capsid

Neither purely helical nor purely icosahedral, and that may possess extra structures such as protein y p ptails or a complex outer wall

Poxvirus

Viral Infection Cycle

Invade a susceptible organism (host)Invade a susceptible organism (host)

Attach to and infect a permissive host cell

Within the host cell the viral genome directs the synthesis of the componentsWithin the host cell, the viral genome directs the synthesis of the components, by cellular machineries, needed for the replication of the viral genome

New viral particles are formed by de novo assembly from newly-synthesized p y y y ycomponents within the host cell

The progeny viral particles are transmitted to new host cells or new organisms

The particles are disassembled inside the new cell, initiating the next infectious cycle

Generalized Model of Viral Replication Cyclep y

Replication of dsDNA Virusp

mRNA proteinsCellular

RNA polymerase II

dsDNA dsDNA

Cellular or viralCellular or viral DNA polymerase

Replication of ssDNA Virusp

mRNA proteins

CellularRNA polymerase II

ssDNA dsDNA

cellular

ssDNA

cellularDNA polymerase

Replication of dsRNA Virusp

proteins

(+)dsRNA (+) ssRNA

Viral RdRp

dsRNA

Viral RdRpViral RdRp Viral RdRp

Replication of (+) ssRNA Virusp ( )

proteins

(+) ( ) (+)(+)ssRNA

(-) ssRNA

Vi l RdR

(+)ssRNA

Vi l RdRViral RdRp Viral RdRp

Replication of (-) ssRNA Virusp ( )

mRNA proteinsViral RdRp

( ) (+)

Viral RdRp

( )(-)ssRNA

(+)ssRNA

Viral RdRp

(-)ssRNA

Vi l RdRViral RdRp Viral RdRp

Replication of Retrovirusp

mRNA proteins

( )

CellularRNA polymerase II

(+)(+) (-)ssDNA dsDNA

Viral

(+)ssRNA

(+)ssRNA

Viralreverse transcriptase

Replication of dsDNA-RT Virus (Hepadnaviridae)(Hepadnaviridae)

mRNA proteinsCellular

( )

RNA polymerase II

( )P ti l P ti ldsDNA (+) ssRNA

(-)ssDNA

PartialdsDNA

PartialdsDNA

Viralreverse transcriptase