VIROLOGYVIROLOGY

Viruses are the smallest Viruses are the smallest infectious agents (20-300 infectious agents (20-300 nanometers)nanometers)

Possess only one kind of nucleic Possess only one kind of nucleic acid, either DNA or RNA as their acid, either DNA or RNA as their genomegenome

Capable of replication only within Capable of replication only within living cells (genetic parasites)living cells (genetic parasites)

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Viral StructureViral Structure

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General Structure of General Structure of VirusesViruses Size range –Size range –

– most <0.2 most <0.2 μμm; requires electron m; requires electron microscopemicroscope

VirionVirion – fully formed virus able to – fully formed virus able to establish an infectionestablish an infection

Prions - misfolded proteins, contain no nucleic acid– cause transmissible spongiform encephalopathies –

fatal neurodegenerative diseases– common in animals:

scrapie in sheep & goats bovine spongiform encephalopathies (BSE), aka mad

cow disease wasting disease humans – Creutzfeldt-Jakob Syndrome (CJS)

Extremely resistant to usual sterilization techniques

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Other noncellular Other noncellular infectious agentsinfectious agents

Satellite virusesSatellite viruses – dependent on – dependent on other viruses for replicationother viruses for replication– adeno-associated virus – replicate only adeno-associated virus – replicate only

in cells infected with adenovirusin cells infected with adenovirus– delta agent – naked strand of RNA delta agent – naked strand of RNA

expressed only in the presence of expressed only in the presence of hepatitis B virushepatitis B virus

ViroidsViroids - short pieces of RNA, no - short pieces of RNA, no protein coat; only been identified in protein coat; only been identified in plants, so farplants, so far

Viral Structure: Viral Structure: CoveringCovering FUNCTIONS:FUNCTIONS:

– Protects the nuclear materialProtects the nuclear material– Responsible for introduction of viral Responsible for introduction of viral

nucleic acid into a suitable host cellnucleic acid into a suitable host cell– Stimulates the immune systemStimulates the immune system

Viral Structure: Viral Structure: Covering - CAPSIDCovering - CAPSID CAPSID: The outer protective shellCAPSID: The outer protective shell

– The most prominent geometric featureThe most prominent geometric feature– Composed of identical protein subunits Composed of identical protein subunits

– CAPSOMERS– CAPSOMERS– Formed by spontaneous self-assembly Formed by spontaneous self-assembly

of capsomersof capsomers

Viral Structure: Naked Viral Structure: Naked VirusesViruses

Viral Structure: Covering Viral Structure: Covering - ENVELOPE- ENVELOPE

Formed when the viral particle Formed when the viral particle carries off a part of the host cell’s carries off a part of the host cell’s membrane (any part of the membrane (any part of the endomembrane system may be endomembrane system may be used)used)

SPIKES or PEPLOMERSSPIKES or PEPLOMERS– Protein spikes protruding through the Protein spikes protruding through the

envelope from the capsidenvelope from the capsid– Essential for attachment to the next hostEssential for attachment to the next host

Viral Structure: Viral Structure: Enveloped VirusesEnveloped Viruses

Viral Structure: Central Viral Structure: Central Core – Nucleic Acids Core – Nucleic Acids

Genetic material Genetic material of the particleof the particle

Viruses may Viruses may contain either contain either DNA or RNA DNA or RNA BUT BUT NOT BOTHNOT BOTH

DNA or RNA DNA or RNA may may exist as single or exist as single or double-strandeddouble-stranded

Viral MorphologyViral Morphology

HelicalHelical IcosahedralIcosahedral

Viral MorphologyViral Morphology

EnvelopedEnveloped ComplexComplex

Modes of Viral MultiplicationModes of Viral Multiplication

AdsorptionAdsorption - binding of virus to specific - binding of virus to specific molecule on host cellmolecule on host cell

PenetrationPenetration - genome enters host cell - genome enters host cell UncoatingUncoating – the viral nucleic acid is – the viral nucleic acid is

released from the capsidreleased from the capsid SynthesisSynthesis – viral components are – viral components are

producedproduced AssemblyAssembly – new viral particles are – new viral particles are

constructedconstructed ReleaseRelease – assembled viruses are released – assembled viruses are released

by budding (exocytosis) or cell lysisby budding (exocytosis) or cell lysis

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ReleaseRelease buddingbudding – exocytosis; nucleocapsid – exocytosis; nucleocapsid

binds to membrane which pinches off binds to membrane which pinches off and sheds the viruses gradually; cell is and sheds the viruses gradually; cell is not immediately destroyednot immediately destroyed

lysislysis – nonenveloped and complex – nonenveloped and complex viruses released when cell dies and viruses released when cell dies and rupturesruptures

Number of viruses released is variableNumber of viruses released is variable– 3,000-4,000 released by poxvirus3,000-4,000 released by poxvirus– >100,000 released by poliovirus>100,000 released by poliovirus

Cytopathic effectsCytopathic effects - virus-induced - virus-induced damage to cells damage to cells

Changes in size & shapeChanges in size & shape Cytoplasmic inclusion bodiesCytoplasmic inclusion bodies Nuclear inclusion bodiesNuclear inclusion bodies Cells fuse to form multinucleated Cells fuse to form multinucleated

cells.cells. Cell lysisCell lysis Alter DNAAlter DNA Transform cells into cancerous cellsTransform cells into cancerous cells

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Persistent InfectionsPersistent Infections Persistent infectionsPersistent infections - cell harbors the - cell harbors the

virus and is not immediately lysedvirus and is not immediately lysed Can last weeks or host’s lifetime; several Can last weeks or host’s lifetime; several

can periodically reactivate – can periodically reactivate – chronic chronic latent statelatent state– measles virus – may remain hidden in brain measles virus – may remain hidden in brain

cells for many yearscells for many years– herpes simplex virus – cold sores and genital herpes simplex virus – cold sores and genital

herpesherpes– herpes zoster virus – chickenpox and shinglesherpes zoster virus – chickenpox and shingles

20 Some animal viruses enter host cell and Some animal viruses enter host cell and

permanently alter its genetic material resulting in permanently alter its genetic material resulting in cancer – cancer – transformation transformation of the cell.of the cell.

Transformed cells have increased rate of growth, Transformed cells have increased rate of growth, alterations in chromosomes, and capacity to divide alterations in chromosomes, and capacity to divide for indefinite time periods resulting in tumors.for indefinite time periods resulting in tumors.

Mammalian viruses capable of initiating tumors are Mammalian viruses capable of initiating tumors are called called oncovirusesoncoviruses. . – Papillomavirus – cervical cancerPapillomavirus – cervical cancer– Epstein-Barr virus – Burkitt’s lymphomaEpstein-Barr virus – Burkitt’s lymphoma

22Lysogeny Lysogeny

Lysogeny results in the spread of the Lysogeny results in the spread of the virus without killing the host cell.virus without killing the host cell.

Phage genes in the bacterial Phage genes in the bacterial chromosome can cause the production chromosome can cause the production of toxins or enzymes that cause of toxins or enzymes that cause pathology – pathology – lysogenic conversion.lysogenic conversion.– Corynebacterium diphtheriaeCorynebacterium diphtheriae – Vibrio choleraeVibrio cholerae– Clostridium botulinumClostridium botulinum

LysogenyLysogeny

Modes of entryModes of entry

Respiratory tract though Respiratory tract though inhalationinhalation

Gastrointestinal tractGastrointestinal tract SkinSkin SexualSexual Direct contactDirect contact Transfusion of bloodTransfusion of blood

Effects of virus on the Effects of virus on the host cellhost cell CPE or cellular effectCPE or cellular effect Transformation of normal cell to Transformation of normal cell to

malignant cellmalignant cell Latent infectionLatent infection Clumping of RBCClumping of RBC

Some of the Medically Some of the Medically Important VirusesImportant Viruses

FamilyFamily GenusGenus Common Common Name of Name of Genus Genus

MembersMembers

DiseaseDisease

DNA VirusesDNA Viruses

HerpesviridaeHerpesviridae SimplexvirusSimplexvirus Herpes Herpes simplex 1&2 simplex 1&2 virusvirus

Cold sores, Cold sores, genital genital herpesherpes

Varicella Varicella zoster viruszoster virus

Chicken poxChicken pox

AdenoviridaeAdenoviridae MastadenovirMastadenovirusus

Human Human adenovirusadenovirus

Colds, URIColds, URI

PapovaviridaPapovaviridaee

PapillomaviruPapillomaviruss

Human Human papillomavirupapillomavirus (HPV)s (HPV)

WartsWarts

HepadnaviridHepadnaviridaeae

HepadnavirusHepadnavirus Hepatits B Hepatits B virusvirus

Serum Serum hepatitishepatitis

Some of the Medically Some of the Medically Important VirusesImportant VirusesFamilyFamily GenusGenus Common Common

Name of Name of Genus Genus

MembersMembers

DiseaseDisease

RNA VirusesRNA Viruses

PicornaviridaePicornaviridae Enterovirus Enterovirus PoliovirusPoliovirus PoliomyelitisPoliomyelitis

HepatovirusHepatovirus Hepatitis A Hepatitis A virusvirus

Short-term Short-term hepatitishepatitis

RhinovirusRhinovirus Human Human rhinovirusrhinovirus

Common coldsCommon colds

TogaviridaeTogaviridae AlphavirusAlphavirus Rubella virusRubella virus German German measlesmeasles

FlaviviridaeFlaviviridae FlavivirusFlavivirus Dengue fever Dengue fever virusvirus

Dengue feverDengue fever

FiloviridaeFiloviridae FilovirusFilovirus Ebola virusEbola virus Ebola feverEbola fever

OrthomyxoviriOrthomyxoviridaedae

Influenza virusInfluenza virus Influenza virusInfluenza virus InfluenzaInfluenza

ParamyxoviridParamyxoviridaeae

ParamyxovirusParamyxovirus Measles virusMeasles virus MeaslesMeasles

RhabdoviridaeRhabdoviridae Lyssavirus Lyssavirus Rabies virusRabies virus RabiesRabies

RetroviridaeRetroviridae LentivirusLentivirus HIVHIV AIDSAIDS

CoronaviridaeCoronaviridae CoronavirusCoronavirus SARS virusSARS virus SARSSARS

RNA VIRUSRNA VIRUS

PicornavirusPicornavirus– Entero virusEntero virus

Arbo virusArbo virus– AlphaAlpha– Flavi virusFlavi virus

Myxo virusMyxo virus– ParamyxovirusParamyxovirus– OrthomyxovirusOrthomyxovirus– pseudomyxoviruspseudomyxovirus

Rhabdo virusRhabdo virus

Picorna virusPicorna virus

– Smallest RNA virusSmallest RNA virus– Single strand RNASingle strand RNA

ENTEROVIRUSENTEROVIRUS

Coxsackie virusCoxsackie virus Enteric human pathogenic orphanEnteric human pathogenic orphan

COXSACKIE VIRUSCOXSACKIE VIRUS

POLIO VIRUSPOLIO VIRUS

Paralysis or poliomyelitisParalysis or poliomyelitis Septic meningitis with no Septic meningitis with no

paralysisparalysis OPVOPV Salk vaccineSalk vaccine

Polio virusPolio virus

POLIOMYELITISPOLIOMYELITIS

Dengue virusDengue virus

Dengue feverDengue fever Breakbone feverBreakbone fever JBEJBE Yellow fever virusYellow fever virus Chikungunya virusChikungunya virus West Nile fever virusWest Nile fever virus Murray valley encephalitis virusMurray valley encephalitis virus

Myxo virusMyxo virus

ParamyxovirusParamyxovirus– Mumps virusMumps virus– Endemic parotitisEndemic parotitis

MUMPSMUMPS

GENERAL DETAILSGENERAL DETAILS

Virus related to Measles virusVirus related to Measles virus MAN ONLY HOSTMAN ONLY HOST ONE SEROTYPEONE SEROTYPE SUB-CLINICAL INFECTIONSSUB-CLINICAL INFECTIONS CONTAGIOUS BEFORE AND CONTAGIOUS BEFORE AND

AFTER SYMPTOMSAFTER SYMPTOMS Affects the Parotid glands Affects the Parotid glands

(Viral Parotitis) and may cause (Viral Parotitis) and may cause orchitis that may lead to orchitis that may lead to infertilityinfertility

PreventionPrevention– LIVE ATTENUATED LIVE ATTENUATED

VACCINEVACCINE– DOES NOT SPREAD DOES NOT SPREAD

TO CONTACTSTO CONTACTS– Contradindicated inContradindicated in

immune-immune-suppressedsuppressed

pregnant womenpregnant women

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OrthomyxovirusOrthomyxovirus– Parainfluenza virusParainfluenza virus– Respiratory syncitial virusRespiratory syncitial virus– RhinovirusRhinovirus– coronaviruscoronavirus

CORONAVIRIDAECORONAVIRIDAE

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Severe Acute Respiratory Syndrome-Severe Acute Respiratory Syndrome-Associated Coronavirus (SARS)Associated Coronavirus (SARS)

Newly emerging disease – 2002Newly emerging disease – 2002 Transmitted through droplet or direct contactTransmitted through droplet or direct contact Fever, body aches, and malaiseFever, body aches, and malaise May or may not experience respiratory symptoms May or may not experience respiratory symptoms

with breathing problems; severe cases can result with breathing problems; severe cases can result in respiratory distress and deathin respiratory distress and death

Diagnosis relies on exclusion of other likely Diagnosis relies on exclusion of other likely agents.agents.

Treatment is supportive.Treatment is supportive.

AVIAN’S FLUAVIAN’S FLU

Influenza VirusInfluenza Virus

Pseudomyxovirus Pseudomyxovirus

RubeolaRubeola– MeaslesMeasles– Koplick’s spots ( oral lesion )Koplick’s spots ( oral lesion )– SSPESSPE

Rubella Rubella – German measlesGerman measles– Transplacental Transplacental

RUBELLA VIRUSRUBELLA VIRUS

TOGAVIRUS FAMILYTOGAVIRUS FAMILY– Alphavirus genus Alphavirus genus – Rubivirus genusRubivirus genus

AEROSOLAEROSOL CHILDREN, ADULTSCHILDREN, ADULTS

– mildmild FETUSFETUS

– can be severecan be severe

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RubellaRubellaTwo clinical forms:Two clinical forms: Postnatal rubella – malaise, fever, sore Postnatal rubella – malaise, fever, sore

throat, lymphadenopathy, rash, generally throat, lymphadenopathy, rash, generally mild, lasting about 3 daysmild, lasting about 3 days

Congenital rubella – infection during 1Congenital rubella – infection during 1stst trimester most likely to induce miscarriage trimester most likely to induce miscarriage or multiple defects such as cardiac or multiple defects such as cardiac abnormalities, ocular lesions, deafness, abnormalities, ocular lesions, deafness, mental and physical retardationmental and physical retardation

Diagnosis based on serological testingDiagnosis based on serological testing No specific treatment availableNo specific treatment available Attenuated viral vaccine MMRAttenuated viral vaccine MMR

SYMPTOMSSYMPTOMS SORE THROAT, RUNNY SORE THROAT, RUNNY

NOSE, COUGHNOSE, COUGH FEVERFEVER RASH, MINOR, RASH, MINOR,

IRREGULARIRREGULAR– lasts 12hour to 5dayslasts 12hour to 5days– not always seennot always seen

ARTHRALGIA, ARTHRITISARTHRALGIA, ARTHRITIS– especially in adults, especially in adults,

especially womenespecially women LYMPHOADENOPATHYLYMPHOADENOPATHY

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EFFECTS ON FETUSEFFECTS ON FETUS HEARING LOSSHEARING LOSS CONGENITAL HEART CONGENITAL HEART

DEFECTSDEFECTS NEUROLOGICALNEUROLOGICAL

– PYSCHOMOTOR PYSCHOMOTOR AND/OR MENTAL AND/OR MENTAL RETARDATIONRETARDATION

OPHTHALMICOPHTHALMIC– CATARACT, CATARACT,

GLAUCOMA, GLAUCOMA, RETINOPATHYRETINOPATHY

thrombocytopeniathrombocytopenia hepatomegalyhepatomegaly splenomegalysplenomegaly intrauterine intrauterine

growth retardationgrowth retardation bone lesionsbone lesions pneumonitispneumonitis

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PREVENTIONPREVENTION LIVE ATTENUATED VACCINELIVE ATTENUATED VACCINE

– DOES NOT SPREAD TO FAMILY DOES NOT SPREAD TO FAMILY MEMBERSMEMBERS

– CHILDREN CHILDREN – SUSCEPTIBLE NON-PREGANT SUSCEPTIBLE NON-PREGANT

FEMALESFEMALES

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Transplacental effectTransplacental effect

Possible chromosomal breakagePossible chromosomal breakage Inhibition of normal mitosisInhibition of normal mitosis DeafnessDeafness Congenital heart diseaseCongenital heart disease Cerebral damageCerebral damage Mental retardationMental retardation Occasionally glaucomaOccasionally glaucoma

RubeolaRubeola

RubellaRubella

rhabdovirusrhabdovirus

RabiesRabies Human vaccineHuman vaccine

– Human diploid cellHuman diploid cell– DEV- Duck’s embryo vaccineDEV- Duck’s embryo vaccine

Animal vaccineAnimal vaccine– Flurry stainFlurry stain– Street Alabama dufferin strainStreet Alabama dufferin strain

Heller stainHeller stain Negri bodiesNegri bodies

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RabiesRabies Virus enters through bite, grows at Virus enters through bite, grows at

trauma site for a week and multiplies, trauma site for a week and multiplies, then enters nerve endings and then enters nerve endings and advances toward the ganglia, spinal advances toward the ganglia, spinal cord and brain.cord and brain.

Infection cycle completed when virus Infection cycle completed when virus replicates in the salivary glandsreplicates in the salivary glands

Clinical phases of Clinical phases of rabies:rabies:

Prodromal phase – fever, nausea, Prodromal phase – fever, nausea, vomiting, headache, fatigue; some vomiting, headache, fatigue; some experience pain, burning, tingling experience pain, burning, tingling sensations at site of woundsensations at site of wound

Furious phase – agitation, Furious phase – agitation, disorientation, seizures, twitching, disorientation, seizures, twitching, hydrophobiahydrophobia

Dumb phase – paralyzed, disoriented, Dumb phase – paralyzed, disoriented, stuporousstuporous

Progress to coma phase, resulting in Progress to coma phase, resulting in deathdeath

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DNA VIRUSDNA VIRUS

AdenovirusAdenovirus Pox virusPox virus Herpes virusHerpes virus Human papova virusHuman papova virus Hepatitis virusHepatitis virus

Adenovirus Adenovirus

TonsilitisTonsilitis AdenitisAdenitis Mild respiratory illnessMild respiratory illness CoryzaCoryza coughcough

ADENOVIRUS ADENOVIRUS

Pox virusPox virus

Small pox ( variola major )Small pox ( variola major ) Alastrim ( variola minor )Alastrim ( variola minor )

SMALL POXSMALL POX

Herpes virusHerpes virus

Herpes simple type AHerpes simple type A– GingivomastitisGingivomastitis– Vesicular eruption of the membrane Vesicular eruption of the membrane

of oral cavityof oral cavity Herpes simplex type BHerpes simplex type B

– VulvovaginitisVulvovaginitis– Danger of congenital complication Danger of congenital complication

( liver, CNS)( liver, CNS)

Genital Herpes Genital Herpes TransmissionTransmission Major routes: sexual & mother-to-infantMajor routes: sexual & mother-to-infant Most sexual transmission probably occurs Most sexual transmission probably occurs

when index case is asymptomaticwhen index case is asymptomatic Efficiency of transmission is greater from Efficiency of transmission is greater from

men to women than women to menmen to women than women to menu Mertz, et al: 144 serodiscordant couplesMertz, et al: 144 serodiscordant couplesu Almost 17% man-to-woman transmissionAlmost 17% man-to-woman transmissionu Almost 4% woman-to-man transmissionAlmost 4% woman-to-man transmission

Male Male HerpesHerpes

Female Female HerpesHerpes

Latex condoms, when used Latex condoms, when used consistently and correctly, are consistently and correctly, are highly highly effectiveeffective for: for: – HIVHIV

And can And can reduce the riskreduce the risk of: of:– GC, CT, and TrichomonasGC, CT, and Trichomonas– Genital herpes, syphilis, chancroid, and Genital herpes, syphilis, chancroid, and

HPV, HPV, only when the infected areas are only when the infected areas are covered by the condomcovered by the condom

Genital HerpesGenital HerpesCondom EffectivenessCondom Effectiveness

CDC, 2002

GENITAL HERPESGENITAL HERPES

GENITAL HERPESGENITAL HERPES

Genital Herpes (HSV)Genital Herpes (HSV) Transmission:Transmission: skin to skin skin to skin

Symptoms:Symptoms: Prodrome--tingling in legs, buttocks or groinProdrome--tingling in legs, buttocks or groinLesion--itching, blister at infection site;Lesion--itching, blister at infection site;Recurrences vary in frequency and severityRecurrences vary in frequency and severity

Time to onset:Time to onset: 2-20 days 2-20 days

Pregnancy:Pregnancy: 5% transmission when lesions present 5% transmission when lesions present

Diagnosis:Diagnosis: culture, antibody test culture, antibody test

Treatment:Treatment: symptom relief; antivirals effective symptom relief; antivirals effective

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Herpes of the NewbornHerpes of the Newborn HSV-1 and HSV-2HSV-1 and HSV-2 Potentially fatal in the neonate and Potentially fatal in the neonate and

fetusfetus Infant contaminated by mother Infant contaminated by mother

before or during birth; hand before or during birth; hand transmission by mother to infanttransmission by mother to infant

Infection of mouth, skin, eyes, CNSInfection of mouth, skin, eyes, CNS Preventative screening of pregnant Preventative screening of pregnant

women; delivery by C-section if women; delivery by C-section if outbreak at the time of birthoutbreak at the time of birth

HERPES LABIALISHERPES LABIALIS

VaricellaVaricella– Virus of chicken poxVirus of chicken pox– Might lead pneumonitis and Might lead pneumonitis and

encephalitisencephalitis– Herpes zosterHerpes zoster

VARICELLA - ZOSTERVARICELLA - ZOSTER

CHICKENPOX / CHICKENPOX / SHINGLESSHINGLES

CMVCMV– Inclusion mononucleosisInclusion mononucleosis– Liver, kidney and lungsLiver, kidney and lungs– Associated with mild hepatitisAssociated with mild hepatitis– Recognized in congenital conditionRecognized in congenital condition– Oncogenic potentialOncogenic potential

CMV CHILD INFECTIONCMV CHILD INFECTION

EBVEBV– Infectious mononucleosisInfectious mononucleosis– Agent of Burkitt’s lymphomaAgent of Burkitt’s lymphoma– Nasopharyngeal carcinomaNasopharyngeal carcinoma– Oncogenic virusOncogenic virus

HHV5 EPSTEIN BARR VIRUS HHV5 EPSTEIN BARR VIRUS causes INFECTIOUS causes INFECTIOUS MONONUCLEOSIS & MONONUCLEOSIS & BURKITT’S LYMPHOMABURKITT’S LYMPHOMA

HUMAN PAPOVA VIRUSHUMAN PAPOVA VIRUS

Papilloma virusPapilloma virus– Verruca vulgarisVerruca vulgaris– Condylomata acuminataCondylomata acuminata

Polyoma virusPolyoma virus– JV virus ( progressive multifocal JV virus ( progressive multifocal

leucoencephalopathy ) leucoencephalopathy ) – BK virus ( kidney transplant, chronic BK virus ( kidney transplant, chronic

disease )disease )

Papilloma virusPapilloma virus

Verruca vulgarisVerruca vulgaris

Condylomata acuminataCondylomata acuminata

Typical Genital WartsTypical Genital Warts

DOIA Website, 2000

Male HPV Male HPV infectioninfection

Female Female HPV HPV

Polyoma virusPolyoma virus

US&A (v. 2/07) 109

The ABC’s of HepatitisThe ABC’s of Hepatitis

HBV - Hepatitis BHBV - Hepatitis B

Unprotected sex with Unprotected sex with multiple partnersmultiple partners

Sharing needles during Sharing needles during injecting drug useinjecting drug use

From infected mother From infected mother to child during birthto child during birth

Sharps/needle sticksSharps/needle sticks

HBV Transmission

US&A (v. 2/07) 111

HBV Cannot be Spread HBV Cannot be Spread by:by:

Sneezing or Sneezing or coughingcoughing

Kissing or huggingKissing or hugging Breast feedingBreast feeding Food or waterFood or water Sharing eating Sharing eating

utensils or utensils or drinking glassesdrinking glasses

Casual contactCasual contact

Hepatitis BHepatitis B

US&A (v.

2/07)

Hepatitis B virus (HBV) is 100 more Hepatitis B virus (HBV) is 100 more infectious than HIVinfectious than HIV

About 5% of Americans have been About 5% of Americans have been infected with HBV at some point infected with HBV at some point during their lifetimeduring their lifetime

People who get infected with HBV People who get infected with HBV can also get infected with Hepatitis can also get infected with Hepatitis D virus (HDV). If this happens, D virus (HDV). If this happens, people often become very sickpeople often become very sick

HCV - Hepatitis CHCV - Hepatitis C

Incubation periodIncubation period Average 6-7 weeksAverage 6-7 weeksRange 2-26 weeksRange 2-26 weeks

No sign or symptomsNo sign or symptoms

Acute illness (jaundice)Acute illness (jaundice)

80%80%

20% (Mild)20% (Mild)

Chronic infectionChronic infectionChronic liver diseaseChronic liver disease

75%-85%75%-85%10%-70% (most are 10%-70% (most are asymptomatic)asymptomatic)

Deaths from chronic Deaths from chronic liver diseaseliver disease 1%-5%1%-5%

ImmunityImmunity No protection from future No protection from future infection identifiedinfection identified

Clinical Features

Age-related

HCV - Hepatitis CHCV - Hepatitis CSymptoms

• flu-like symptoms

• jaundice

• fatigue

• dark urine

• abdominal pain

• loss of appetite

• nausea

• Injecting drug use• Hemodialysis (long-term)• Blood transfusion and/or

organ transplant before 1992

• From infected mother to child during birth

• Occupational exposure to blood - mostly needlesticks

• Sexual or household exposures - rare

HCV Transmission

US&A (v. 2/07) 116

Sources of Infection -- Sources of Infection -- Hepatitis CHepatitis C

Hepatitis CHepatitis C Risk Factors:Risk Factors:

– Long-term kidney Long-term kidney dialysisdialysis

– Sex with multiple Sex with multiple partnerspartners

– Tattooing or body Tattooing or body piercing with piercing with shared needles or shared needles or unsterilized unsterilized equipmentequipment

– Intranasal cocaine Intranasal cocaine use with shared use with shared strawsstraws

Pamela Anderson claims her infection came from a tattoo needle

Etiology of HIVEtiology of HIV

HTLV-III- Human T cell HTLV-III- Human T cell Lymphotrophic virus IIILymphotrophic virus III

LAV- lymphadenopathy- LAV- lymphadenopathy- associated virusassociated virus

* contains single RNA strand and * contains single RNA strand and a DNA synthesizing enzyme a DNA synthesizing enzyme called reverse transcriptasecalled reverse transcriptase

121

Causative AgentCausative Agent Retrovirus, genus LentivirusRetrovirus, genus Lentivirus Encode reverse transcriptase Encode reverse transcriptase

enzyme which makes a double enzyme which makes a double stranded DNA from the single-stranded DNA from the single-stranded RNA genomestranded RNA genome

Viral genes permanently Viral genes permanently integrated into host DNAintegrated into host DNA

Human Immunodeficiency Virus Human Immunodeficiency Virus (HIV) the cause of Acquired (HIV) the cause of Acquired Immunodeficiency Syndrome Immunodeficiency Syndrome (AIDS)(AIDS)

HIV-1 and HIV-2 HIV-1 and HIV-2 T-cell lymphotropic viruses I and T-cell lymphotropic viruses I and

II – leukemia and lymphomaII – leukemia and lymphoma HIV can only infect host cells HIV can only infect host cells

that have the required CD4 that have the required CD4 marker plus a coreceptor.marker plus a coreceptor.

Legend Legend

Th- T- helperTh- T- helper MCH- major histocompatibility MCH- major histocompatibility

complexcomplex CTL- cytotoxic T cellCTL- cytotoxic T cell

Cells of the immune Cells of the immune system ( review )system ( review ) B- cellsB- cells

– Plasma cellsPlasma cells– Memory cellsMemory cells

T- cellsT- cells

Helper T cellsHelper T cells ( (effector T cellseffector T cells or or Th Th cellscells) are the "middlemen" of the ) are the "middlemen" of the adaptive immune systemadaptive immune system. Once . Once activated, they divide rapidly and activated, they divide rapidly and secrete small proteins called secrete small proteins called cytokinescytokines that regulate or assist in the immune that regulate or assist in the immune response. Depending on the size, response. Depending on the size, cytokine signals received, these cells cytokine signals received, these cells differentiate into differentiate into TH1TH1, , TH2TH2, , TH3TH3, , TH17TH17,,THFTHF, or one of other subsets, which , or one of other subsets, which secrete different cytokines. secrete different cytokines. CD4+CD4+ cells cells are associated with are associated with MHC class IIMHC class II..

About T-helperAbout T-helper

T helper cellsT helper cells (also known as (also known as effector T cellseffector T cells or or Th cellsTh cells) are ) are a sub-group of lymphocytes (a a sub-group of lymphocytes (a type of white blood cell or type of white blood cell or leukocyte) that play an important leukocyte) that play an important role in establishing and role in establishing and maximizing the capabilities of the maximizing the capabilities of the immune system. immune system.

they have no cytotoxic or they have no cytotoxic or phagocytic activity; they cannot phagocytic activity; they cannot kill infected host (also known as kill infected host (also known as somatic) cells or pathogens, somatic) cells or pathogens,

Th cells are involved in activating Th cells are involved in activating and directing other immune cells, and directing other immune cells, and are particularly important in and are particularly important in the immune system the immune system

Mature Th cells are believed to Mature Th cells are believed to always express the surface always express the surface protein CD4. T cells expressing protein CD4. T cells expressing CD4 are also known as CD4 are also known as CD4+ T CD4+ T cellscells. .

CytotoxicCytotoxic T cells T cells (TC cells, or CTLs) destroy (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are virally infected cells and tumor cells, and are also implicated in also implicated in transplanttransplant rejection. These rejection. These cells are also known as cells are also known as CD8+ T cells (associated CD8+ T cells (associated with MHC class Iwith MHC class I), since they express the ), since they express the CD8CD8 glycoprotein at their surface. Through SLOB[glycoprotein at their surface. Through SLOB[clarificationclarification needed needed] interaction with T ] interaction with T regulatory CD4+CD25+FoxP3+ cells, these cells regulatory CD4+CD25+FoxP3+ cells, these cells can be inactivated to a anergic state, which can be inactivated to a anergic state, which prevent prevent autoimmuneautoimmune diseases such as diseases such as experimental autoimmune encephalomyelitisexperimental autoimmune encephalomyelitis..[1][1]

Memory T cellsMemory T cells are a subset of antigen- are a subset of antigen-specific T cells that persist long-term specific T cells that persist long-term after an infection has resolved. They after an infection has resolved. They quickly expand to large numbers of quickly expand to large numbers of effector T cells upon re-exposure to effector T cells upon re-exposure to their cognate antigen, thus providing their cognate antigen, thus providing the immune system with "memory" the immune system with "memory" against past infections. Memory T cells against past infections. Memory T cells comprise two subtypes: comprise two subtypes: central central memory T cells (TCM cells) and effector memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+.cells may be either CD4+ or CD8+.

Regulatory T cellsRegulatory T cells (Treg cells), formerly known as (Treg cells), formerly known as suppressor T cellssuppressor T cells, are crucial for the maintenance of , are crucial for the maintenance of immunological tolerance. Their major role is to shut down immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been Two major classes of CD4+ regulatory T cells have been described, including the described, including the naturally occurring Treg cells naturally occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg and the adaptive Treg cells. Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) cells (also known as CD4+CD25+FoxP3+ Treg cells) arise arise in the thymus, whereas the adaptive Treg cells (also in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of of an intracellular molecule called FoxP3. Mutations of the the FOXP3FOXP3 gene can prevent regulatory T cell gene can prevent regulatory T cell development, causing the fatal autoimmune disease development, causing the fatal autoimmune disease

Natural killer T cellsNatural killer T cells (NKT cells) are a (NKT cells) are a special kind of lymphocyte that bridges the special kind of lymphocyte that bridges the adaptive immune system with the innate adaptive immune system with the innate immune system. Unlike conventional T cells immune system. Unlike conventional T cells that recognize peptide antigen presented by that recognize peptide antigen presented by major histocompatibility complex (MHC) major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid molecules, NKT cells recognize glycolipid antigen presented by a molecule called antigen presented by a molecule called CD1d. Once activated, these cells can CD1d. Once activated, these cells can perform functions ascribed to both Th and Tc perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cells (i.e., cytokine production and release of cytolytic/cell killing molecules).cytolytic/cell killing molecules).

γδ T cellsγδ T cells (gamma delta (gamma delta T cellsT cells) represent a small ) represent a small subset of T cells that possess a distinct T cell receptor subset of T cells that possess a distinct T cell receptor (TCR) on their surface. A majority of T cells have a TCR (TCR) on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- composed of two glycoprotein chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes lymphocytes known as intraepithelial lymphocytes (IELs). The antigenic molecules that activate γδ T cells (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting presented by MHC molecules on antigen presenting cells. cells.

HIV and AIDSHIV and AIDSThe Cellular PictureThe Cellular Picture

In advanced disease: the loss of another cell type

CD8+ cytotoxic killer cells

Loss of one cell type throughout the course of the disease

CD4+ T4 helper cells

A fall in the CD4+ cells always precedes disease

Suggests an infectious agent

A virus

But initially difficult to grow

Rapidly kills cells on which it grows

• AIDS is therefore the end point of an infection that is continuous, progressive and pathogenic

• With the prevalence of HIV in the developing world, HIV and its complications will be with us for generations

AIDS DefinitionAIDS DefinitionAIDS DefinitionAIDS Definition• AIDS is currently defined as the presence of one of 25 conditions indicative of severe immunosuppression

OR• HIV infection in an individual with a CD4+ cell count of <200 cells per cubic mm of blood

HIV and AIDSHIV and AIDS

The cellular and immunological picture

The course of the disease

1. Acute Infection • High virus titer

• Mild symptoms

• Fall in CD4+ cells but recovers

• Rise in CD8+ cells but recovers

• A high virus titer (up to 10 million viruses per ml blood)

• Macrophages infectedMacrophages bring HIV into the body if sexually transmitted

HIV and AIDSHIV and AIDS

2. A strong immune response

Virus almost disappears from circulation

• Good cytoxic T cell response

• Soluble antibodies appear later against both surface and internal proteins

• Most virus at this stage comes from recently activated (dividing) and infected CD4+ cells

• CD4+ cell production compensates for loss due to lysis of cells by virus production and destruction of infected cells by CTLs

HIV and AIDSHIV and AIDS3. A latent state

Latency of virus and of symptoms

• Virus persists in extra-vascular tissues

• Lymph node dendritic cells

• Resting CD4+ memory cells (last a very long time - a very stable population of cells) carry provirus

HIV and AIDSHIV and AIDS

• 10 billion HIV particles per day

• Virus half life 5.7 hours

• 100-10 million virions per ml blood (set point)

• Small minority of T4 cells are infected

• Virus found in lymph nodes

HIV and AIDSHIV and AIDS4. The beginning of disease

Massive loss of CD4+ cells

• CD4+ cells are the targets of the virus

• Cells that proliferate to respond to the virus are killed by it

• Dendritic cells present antigen and virus to CD4 cells

• Epitope variation allows more and more HIV to escape from immune response just as response wanes

• Apoptosis of CD4+ cells

• HIV patients with high T4 cell countsHIV patients with high T4 cell counts do not develop AIDS do not develop AIDS

HIV and AIDSHIV and AIDS5. Advanced disease - AIDS

CD8+ cells destroy more CD4+ cells

• CD4 cell loss means virus and infected cells no longer controlled

• As CD4+ cells fall below 200 per cu mmvirus titer rises rapidly and remaining immune response collapses

• CD8+ cell number collapses

• Opportunistic infections

• Death in ~2 years without intervention

143

Epidemiology of HIV Epidemiology of HIV InfectionsInfections Transmission occurs by direct and Transmission occurs by direct and

specific routes: mainly through specific routes: mainly through sexual intercourse and transfer of sexual intercourse and transfer of blood or blood products; babies can blood or blood products; babies can be infected before or during birth, be infected before or during birth, and from breast feeding.and from breast feeding.

HIV does not survive long outside of HIV does not survive long outside of the body.the body.

Men account for 70% of new Men account for 70% of new infections.infections.

Anal sex provides an entrance for Anal sex provides an entrance for the virus.the virus.

IV drug abusers can be HIV carriers; IV drug abusers can be HIV carriers; significant factor in spread to significant factor in spread to heterosexual populationheterosexual population

145

Insert figure 25.14HIV routes of infection

146

Pathogenesis and Virulence Pathogenesis and Virulence Factors of HIVFactors of HIV

HIV enters through mucous HIV enters through mucous membrane or skin and travels to membrane or skin and travels to dendritic phagocytes beneath the dendritic phagocytes beneath the epithelium, multiplies and is shed.epithelium, multiplies and is shed.

Virus is taken up and amplified by Virus is taken up and amplified by macrophages in the skin, lymph macrophages in the skin, lymph organs, bone marrow, and blood.organs, bone marrow, and blood.

HIV attaches to CD4 and HIV attaches to CD4 and coreceptor; HIV fuses with cell coreceptor; HIV fuses with cell membrane.membrane.

Reverse transcriptase makes a Reverse transcriptase makes a DNA copy of RNA. DNA copy of RNA.

Viral DNA is integrated into host Viral DNA is integrated into host chromosome (provirus).chromosome (provirus).

Can produce a lytic infection or Can produce a lytic infection or remain latentremain latent

Inexorable decline of Inexorable decline of CD4+ T4 cellsCD4+ T4 cellsInexorable decline of Inexorable decline of CD4+ T4 cellsCD4+ T4 cells

Of great importance to therapeutic strategy

Why do all of the T4 cells disappear?

At early stages of infection

only 1 in 10,000 cells is infected

Late 1 in 40

But few cells are infected:

Early stage of infection 1:10,000

Late 1:40

Why do all T4 Why do all T4 cells cells disappear? disappear?

1. PUNCTURED MEMBRANE

Virus destroys the cell as a result of budding

But syncytia not common

Most T4 cells are not HIV+

Could “sweep up” uninfected cells

Uninfected CD4 cell

Gp120 negative

Cells Fuse

Killing of CD4 cells2. Syncytium

Formation

Infected CD4 cell

Gp120 positive

Why do all T4 cells Why do all T4 cells disappear? - 2disappear? - 2

Cytotoxic T cell

Killing of CD4 cells3. Cytotoxic T cell-mediated

lysis

Why do all T4 Why do all T4 cells cells disappear? disappear?

BUT: Most cells are not infected

Killing of CD4+ cells4. Binding of free Gp120

to CD4 antigen makes uninfected T4 cell look

like an infected cellComplement-mediated

lysis

Could account for the loss of uninfected T4 cells

Killing of CD4+ cells4. Binding of free Gp120

to CD4 antigen makes uninfected T4 cell look

like an infected cellComplement-mediated

lysis

Could account for the loss of uninfected T4 cells

Binding to CXCR4 results

in expression of TNF-alpha on

the cell surface

?G protein

signal

?

Binding to CXCR4 results in

expression of TNF-alpha receptor II

CD8 cell (no CD4 antigen)

Macrophage

CXCR4 chemokine receptor

HIVgp120

chemokine

Why do all T4 cells Why do all T4 cells disappear?disappear?

Induction of apoptosis

CD8 cell

MacrophageCXCR4

Death

CD8 T cell apoptotic

bodies

Why do all T4 cells Why do all T4 cells disappear?disappear?

Induction of apoptosis

Macrophages may be Macrophages may be infected by two routesinfected by two routesMacrophages may be Macrophages may be infected by two routesinfected by two routes

CD4

Fc receptor

HIV gp120 binds to macrophage CD4 antigen

Virus is opsonized by anti gp120 antibodies which bind to macrophage Fc receptors - an enhancing antibody

HIV gp120

HIV

Anti-gp120 vaccine problemvaccine problem

156

Primary effects of HIV infection:Primary effects of HIV infection:– extreme leukopenia – lymphocytes in extreme leukopenia – lymphocytes in

particularparticular– formation of giant T cells and other syncytia formation of giant T cells and other syncytia

allowing the virus to spread directly from cell allowing the virus to spread directly from cell to cellto cell

– Infected macrophages release the virus in Infected macrophages release the virus in central nervous system, with toxic effect, central nervous system, with toxic effect, inflammation.inflammation.

Secondary effects of HIV:Secondary effects of HIV:– Destruction on CD4 lymphocytes allows for Destruction on CD4 lymphocytes allows for

opportunistic infections and malignancies.opportunistic infections and malignancies.

157

Signs and Symptoms of HIV Signs and Symptoms of HIV Infections and AIDSInfections and AIDS

Symptoms of HIV are directly related Symptoms of HIV are directly related to viral blood level and level of T to viral blood level and level of T cells.cells.

Initial infection – mononucleosis-like Initial infection – mononucleosis-like symptoms that soon disappearsymptoms that soon disappear

Asymptomatic phase 2-15 years Asymptomatic phase 2-15 years (avg. 10)(avg. 10)

Antibodies are detectable 8-16 Antibodies are detectable 8-16 weeks after infection.weeks after infection.

HIV destroys the immune system.HIV destroys the immune system. When T4 cell levels fall below 200/When T4 cell levels fall below 200/L L

AIDS symptoms appear including AIDS symptoms appear including fever, swollen lymph nodes, fever, swollen lymph nodes, diarrhea, weight loss, neurological diarrhea, weight loss, neurological symptoms, opportunistic infections symptoms, opportunistic infections and cancers.and cancers.

159

Diagnosis of HIV Diagnosis of HIV InfectionInfection Testing based on detection of Testing based on detection of

antibodies specific to the virus in antibodies specific to the virus in serum or other fluids; done at 2 serum or other fluids; done at 2 levelslevels

Initial screeningInitial screening– ELISA, latex agglutination and rapid ELISA, latex agglutination and rapid

antibody testsantibody tests– rapid results but may result in false rapid results but may result in false

positivespositives

Follow up with Western blot Follow up with Western blot analysis to rule out false analysis to rule out false positivespositives

False negatives can also occur; False negatives can also occur; persons who may have been persons who may have been exposed should be tested a exposed should be tested a second time 3-6 months later.second time 3-6 months later.

161

Insert Table 25.A page 776AIDS-defining illnesses

162

Preventing and Treating Preventing and Treating HIVHIV

No vaccine availableNo vaccine available– monogamous sexual relationshipsmonogamous sexual relationships– condomscondoms– universal precautionsuniversal precautions

No cure; therapies slow down No cure; therapies slow down the progress of the disease or the progress of the disease or diminish the symptomsdiminish the symptoms– inhibit viral enzymes: reverse inhibit viral enzymes: reverse

transcriptase, protease, integrasetranscriptase, protease, integrase– inhibit fusioninhibit fusion– inhibit viral translationinhibit viral translation– highly active anti-retroviral therapyhighly active anti-retroviral therapy

HIVHIV