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Chapter 18Eucaryotic Viruses and other

acellular infectious agents11-25-200811-26-2008

Copyright © The McGraw-Hill

Companies, Inc. Permission requiredfor reproduction or

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Taxonomy of Eucaryotic Viruses

most of the ~5,000 known viruses infect eucaryotic organisms Virus classification by the ICTV

Genome structureReplication strategyMorphologyGenetic relatedness



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Viruses that Infect Vertebrates

Figure 18.1



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Reproduction of Animal Viruses

adsorptionpenetration and uncoatingreplication of virus nucleic acidssynthesis and assembly of virionsvirion release



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Table 18.1



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Penetration and Uncoating

fusion of envelope with host cell membrane

Fig 18.4



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Endocytosis – enveloped virus

Figure 18.4 (b)



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Endocytosis – naked virus

Figure 18.4 (c)



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Replication and transcription in DNA Viruses- Herpes simplex virus I

uses host RNApolymerase forsynthesis of viralmRNA

uses virus-encoded DNApolymerase forgenome replication

Figure 18.6



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Poxviruses

large, morphologically complex double-stranded DNA (dsDNA) virusesvirion carries DNA-dependent RNA polymerase that synthesizes early mRNA

encodes DNA polymerase and other enzymes needed for DNA replication

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Hepadnaviruses- HBV

circular, partial dsDNA genometranscribed by host RNAP

generates several mRNA moleculesone for pregenome RNA others encode polymerase with reverse transcriptase activity

pregenome converted to dsDNA by virus polymerase (+RNA -DNA 2S DNA)

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Replication and Transcription in RNA Viruses

very diverse reproductive strategiesfour general modes of replication and transcription



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Pico-RNA

Para- and ortho-Myxo- affinity to mucin

Respiratory-enteric-orphan



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Assembly of Virus Capsids

late genes direct capsid protein synthesis which spontaneously self-assemble to form the capsidduring icosahedral virus assembly empty procapsids form first, nucleic acid are then insertedassembly of envelope viruses

in most cases, similar to assembly of naked viruses

site of morphogenesis varies



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Figure 18.2



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Virion Release

naked virusesusually by lysis of host cell

envelope virusesformation of envelope and release usually occur concurrently (budding)

virus-encoded proteins incorporated into host membranenucleocapsid buds outward and is surrounded by modified host membrane



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Release of influenza virus by budding

Figure 18.11



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HIV release by budding

Figure 18.12 (a)



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Mechanisms of host cell damage and cell death

inhibition of host DNA, RNA, and protein synthesislysosome damage

causes release of hydrolytic enzymes alteration of plasma membrane

lead to attack of host by immune systemlead to cell fusion, forming syncytium



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Other mechanisms…toxicity from high concentrations of viral proteinsformation of inclusion bodies

can disrupt cell structurethe Negri bodies in rabies infected neurons

chromosomal disruptionstransform host cell into malignancy

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Types of viral infections (Fig. 18.3)

acute infectionsrapid onset and relatively short duration

persistent infections- last many yearsChronic infection, e.g, HBV infectionLatent infection, e.g., Herpes virus infection-



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Types of persistent infections

chronic virus infectionvirus almost always detectableclinical symptoms mild or absent for long periods

latent virus infectionvirus stops reproducing and remains dormant for some timeduring latency, symptoms, antivirus-antibodies, and viruses are not detectable



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Possible causes of persistent infections

integration of viral genome into host genomedecrease in antigenicity of virusmutation to less virulent and slower reproducing form

defective interfering (DI) particle – deletion mutant that cannot reproduce and slows reproduction of normal virus



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Slow virus diseases

Symptoms take years to emergesubacute sclerosing panencephalitis caused by measles virusHIV infectionsPrion

Prion

A small proteinaceous infectiousparticlePasses through the filter (100 nm)and still transmits diseaseresistant to a wide range of chemical and physical treatment

inactivated at 121oC 1 h



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Prion-caused degenerative diseases

Scrapiebovine spongiform encephalopathy (BSE) or mad cow diseaseCreutzfeldt-Jakob disease (CJD) and variant CJD (vCJD)Kuru

Scrapie- cause intense itching- The prototype of prion- A natural progressive brain disease

Kuru- “shivering” or “ trembling”

1950, occurred in the Fore tribe of New Guinea highlands

Related to the cannibalistic practicesBlurred speech, silly smiles, and dementia

lose the ability to walk, talk, and see

The 1st Nobel Prize for prion study

1976, Carleton Gajdusek (1923~)retired as chief of the laboratory of CNS at NIH

Demonstrated Kuru’s etiology an infectious invisible slow(~ 30 y incubation period) virus as that of Scrapie?Never saw any inflammation!

Creutzfeldt-Jakob disease (CJD)

The human form of mad cow diseaseBSE (Bovine Spongiform encephalopathy)

Identified by Creutzfeldt and Jakob (1920)A progressive fatal neurodegenerative disease Usually aged between 50~75Characterized by seizures, massive in-coordination, dementia

Transmission of CJDInjection with contaminated growth hormoneTransplantation of contaminated corneasContact with contaminated medical devices

brain electrodes- “Iatrogenic”Ingestion of infected tissue

1996 in UK, causes an unusual incidence of CJD in young people (<45 yr)- new variant of CJD/ vCJD

Blood transfusion and spread of vCJD(Emerg Infect Dis 2007)

Inheritable CJD- prnpA Gerstmann-Straussier-Scheinker syndromeA Kuru like familial disease Inherited forms emerge earlier (~ 45 yr)

familial CJD, GSS, fatal familial insomnia (FFI)-10~15%specific mutation of the gene on chromosome 20-prnp



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Current Modelof Disease Production by Prions

PrPC (prion protein): “normal” form PrPSc : abnormal form

entry of PrPSc into animal brain causes PrPC to change its conformation to abnormal formthe newly produced PrPSc convert more to the abnormal forminteractions between PrPSc and PrPC

crosslinking of PrPC neuron loss

The 2nd Nobel prize-Prion pathogenesis

PrPsc binds to the normal PrPc

on the cell surface, causing it to be processed into PrPsc - a replicating protein, to be released from the cell, and to be aggregated as amyloid-like plaques in the brainVacuolated neurons (loss of function and lack of an immune response)

1997, Stanley Prusiner(1942~) for showing that PrPsc is sufficient to cause disease

Director of institute of neurodegenerative disease UCSF



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Viruses and Cancer

tumorgrowth or lump of tissue

neoplasiaabnormal new cell growth and reproduction due to loss of regulation

anaplasiareversion to a more primitive or less differentiated state

metastasisspread of cancerous cells throughout body



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Carcinogenesis

complex, multistep processoften involves oncogenes

cancer-causing genesmany involved in regulation of cell growth and differentiation

some viruses contribute to carcinogenesis



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Viruses implicated in human cancers

Epstein-Barr virus Burkitt’s lymphomanasopharyngeal carcinoma

Hepatitis B virus liver cancer

Hepatitis C virus liver cancer

Human herpesvirus 8 HIV

Kaposi’s sarcoma

human papillomavirus cervical cancer

HTLV-1 and HTLV-2 leukemia

hepatoma



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Possible mechanisms by which viruses cause cancer

carry oncogene into cell and insert it into host genomealtered cell regulation due to changes in kinase activity or production of regulatory proteinsinsertion of promoter or enhancer next to cellular oncogene

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Chapter 37

Human Diseases Caused by Viruses

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Airborne Diseases

when human is source, airborne viruses are propelled from respiratory tract by coughing, sneezing, or vocalizing

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Chickenpox (Varicella)

caused by varicella-zoster virusresults from initial infectionAttenuated vaccine

Figure 37.1

Shingles (herpes zoster)

postherpetic neuralgiareactivated form of chickenpox

Figure 37.2

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Flu or common cold

clinical manifestationschills, fever, headache, malaise, and general muscular aches and painsrecovery usually within 3 to 7 daysoften leads to secondary infections by bacteriarhinitis, tonsillitis, laryngitis, bronchitis, and pneumonia

treatment, prevention, and controlsymptomatic/supportive therapyinactivated virus vaccine

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Influenza (Flu) by influenza virusOrthomyxovirus (segmented virus)

Classified into A, B, and C groups16 HA and 9 NA

Influenza Pandemics1918, HswN1 (Spanish flu)

50~ 100 million moratlity1947, H1N1 1957, H2N2 (Asian flu)1968, H3N2 (Hong Kong flu)1977, H1N1 (Russian flu)Avian flu- H5N1(1997~)

Generation of a reassortant virus - broad host range and segmented genome

Reassortant virus

Avian flu virusH9N2 (1998/1999)

China and Hong Kong

H7N7 (2003) Netherlands

H5N1 in human(1997~2003~)

Hong Kong, China, and worldwide….since 2003, > 300 infected and > 150 died

Emerging Infectious Diseases (2007) October

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SARS (Severe Acute Respiratory Syndrome)

An emerging disease cause by coronavirusFlu-like syndromeVaccine target?- Virus of the year (2002-2003)

Where is the SARS virus?? Box18.1- a mutation in spike protein

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3 groups coronaviruses: groups 1 and 2: mammalian virusesgroup 3 contains only avian viruses

Classified into distinct species by host range, antigenic relationships, and genomic organization

Classification of coronaviruses

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Phylogenetic analyses of SARS-CoV sequences

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Measles (Rubeola)

caused by measles virussubacute sclerosingpanencephalitis

rare progressive degeneration of central nervous system caused by measles virus

treatment, prevention, and control

symptomatic/supportive therapyattenuated measles vaccine

MMR vaccine (measles, mumps, rubella)

Figure 37.3

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Mumps

caused by mumps viruspleomorphic, enveloped virushelical nucleocapsidnegative strand RNA

Figure 37.4

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Rubella (German Measles)

caused by rubella virusssRNA virus

spread by respiratory dropletscongenital rubella syndrome

infection of pregnant women in first trimesterfetal death, premature delivery, and/or congenital defectslive attenuated vaccine: MMR- measles, mumps, rubella

Human immunodeficiency virus (HIV)

1983, HIV was correlated with AIDS (acquired immunodeficiency syndrome)

A retrovirus (an RNA virus) believed to have evolved in Africa from a monkey virus2006 CDC estimation:

~ 1 million HIV infections in USAConverging HIV and MDR-TB (multi-drug resistance tuberculosis) Outbreaks Worsen

HIV

Figure 37.7

TransmissionAcquired and passed from person to person

when infected blood, semen or vaginal secretions come in contact with uninfected person’s broken skin or mucous membranes

Groups most at risk in descending orderhomosexualsintravenous drug usersheterosexuals with drug users and prostituteschildren of infected mothers and breast-fed infantstransfusion patients and transplant recipients

• Once inside host, HIV gp120 envelope protein binds to host CD4+glycoprotein plasma membrane receptor on CD4 + cells

HIV pathogenesis

Figure 37.8

Acquired Immune Deficiency Syndrome (AIDS)caused by human immunodeficiency virus (HIV)

occurs world wide, causing the great pandemic of the second half of the twentieth centuryretrovirustheories on origin of disease

HIV-1 evolved from chimp virus SIVcpzuse of human blood products in chimps infected animals with HIV-1 precursor that evolved into SIVcpz

Course of Disease

some patients rapidly develop clinical AIDS; die within 2-3 yearssome patients remain relatively healthy for at least 10 years post infectionin majority of patients HIV infection progresses to AIDS in 8-10 years

CDC classification for HIV-related stages

AIDS- fourth and last stageimmune system no longer able to defend against virus

definition of AIDSall HIV-infected individuals who has fewer than 200 CD4+ T cells/microliter of blood or a CD4+ cell percentage of lymphocytes of less than 14

AIDS-related cancers

Kaposi’s sarcomacaused by human herpesvirus 8

carcinoma of mouth and rectumB-cell lymphomas

AIDS-related central nervous system disease

headaches, fever, subtle cognitive changes, abnormal reflexes, and ataxiadementia and severe sensory and motor changes observed in advanced casesautoimmune neuropathies, cerebrovasculardisease, and brain tumors are common

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Viral Hepatitishepatitis

inflammation of livercaused by different viruses

Epstein-Barr virus (EBV)cytomegalovirus (CMV)

cause mild, self-resolving diseaseno permanent hepatic damagesigns and symptoms include fatigue, nausea, and malaise

hepatotropic viruses (HAV, HBV, HCV, HDV, HEV, HGV, and ?)

Hepatotropic viruses

Table 37.4

Acute viral Gastroenteritis

Food-borne and waterborne diseases Inflammation of stomach or intestines

important disease of infants and children, leading cause of childhood death in developing countriesprobably spread by fecal-oral route

Figure 37.21 Rotavirus

Enterovirus 71 (1998~ )

An RNA virusTypical cold symptoms

mild enteric diseasehand, foot, and mouth disease

CNS (central nervous syndrome) diseases

Zoonotic (Animal-Borne) Diseases

human viral infections in animal reservoirs before transmission to and between humansmany are on Select Agents list as potential bioweapons

Ebola and Marburg viruseshantavirusesLassa fever virusNipah virus

bio-safety P4 level

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Filoviridae- Marburg and Ebola virus

Ebola hemorrhagic fever A severe and often fatal disease in human or nonhuman primates1st recognition- 19764 subtypes:

Humans- Ebola-Zaire, Ebola-Sudan, and Ebola-Ivory CoastNonhuman Primates- Ebola-Reston

An RNA virus-1967, Marburg

-1976, Ebola/Zaire

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Hantavirus Pulmonary Syndrome

An outbreak occurred in May 1993 in the Four Corners (New Mexico, Arizona, Colorado, and Utah)

The deer mouse- the principal carrier (climate changes)

Navajo IndianNo person to person spread

cause hemorrhagic fever

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Smallpox (Variola)smallpox virusA re-emerging disease: “Biological weapon”

transmitted by aerosol or contact

humans are only reservoir30% fatality

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