Pathophysiology: ID & Micro (Viruses)

Introduction to Virology.......................................................................................................................................................... 2
(+) RNA Viruses ....................................................................................................................................................................... 5
HIV (and retroviruses) ............................................................................................................................................................. 8
Small DNA Viruses: Parvoviruses & Papillomaviruses .......................................................................................................... 12
Influenza: Epidemics, Pandemics, and Prevention Strategies .............................................................................................. 15
Viral gastroenteritis............................................................................................................................................................... 18
Gammaherpesviruses: EBV / KSHV ....................................................................................................................................... 20
Viral Hepatitis........................................................................................................................................................................ 23

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 Introduction to Virology
History: “filterable agent” (not like bacteria); nucleic acid infectious, no binary 3 basic types of virus
fission, requires host, first described in 19th century (agriculture (TMV)  1. Bacteriophage
animals (foot/mouth) humans (yellow fever) 2. Animal/plant (DNA or RNA)
3. Retrovirius (RNADNARNA)
Virion: virus particle (viral nucleic acid + structural proteins)
 Structural proteins = payload vehicle to deliver nucleic acids Properties of viruses
 Example: alphavirus is enveloped, icosahedral
 Small, infectious, obligate
Structural proteins: encoded by viral genome; packaged into virion (protective intracellular parasite
coat for nucleic acid)  Genome: DNA or RNA
 Protein capsid ± lipoprotein envelope (cell membrane of host cell)  In host cell: genome
replicated, synthesis of other
Nonstructural proteins: encoded by viral genome, not packaged into virion virion components via host
 Enzymes (polymerases, helicases, etc) or transcription factors systems, progeny assembled
 Needed for viral replication in cell

Usually nonstructural proteins encoded 1st on genome (5’ end) because they’re needed for translation/transcription

Basic structures: icosahedral / helical; enveloped or non-enveloped Taxonomy:

 Example: picornavirus (common cold). Icosahedral (20 triangular faces, 1. nucleic acid (DNA/RNA; +/-, ds/ss)
12 verteces). 2. capsid (symmetry of protein shell:
 Common motif for icosahedral: 8-stranded antiparallel β-barrel icosahedral/helical)
3. envelope (lipid membrane,
Basic viral genome structures naked/enveloped)
4. dimensions of virion / capsid
(+) strand (sense) Non-segmented
Single stranded Non-segmented
RNA

(-) strand (antisense)

Segmented
Double stranded Segmented
Single stranded
DNA

Linear
Double stranded
Circular

Viruses evolve rapidly; produce large #s progeny; RNApol has no proofreading function (population = “quasispecies”)
 Mutation
 Recombination (two viruses in same cell, recombine)
 Reassortment (2 viruses with segmented genomes in same cell, e.g. flu)

One step growth curves: takes a day or two, then kicks into gear. Many fold higher # organisms than bacteria

Viral replication cycle: attachment, penetration, uncoating, transcription of early mRNA/translation early proteins,
replication of viral DNA, transcription of late mRNA, translation of late proteins, assembly, release.

Cell surface molecules for virus attachment:

 CHOs: linked to proteins/lipids (sialic acid, GAGs)
 Lipids (glycolipids, proteolipids)
 Proteins (immunoglobulin superfamily, C’ –regulatory proteins, integrins, TNF receptor superfamily)

Receptor binding sites: can be depressions (picornavirus “canyons”) or projections (rotavirus “fibers”)
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  Neutralizing antibodies can bind to these receptor sites; block ability to interact with receptor (e.g. bind to
rhinovirus canyon)

Viral genome: all viruses need a strategy to make RNA

 (+) strand RNA viruses: make (-) strand as template to copy, or can undergo direct translation
 (-) strand RNA: need to make (+) strand to copy (have polymerase)
 DNA viruses: need to get into host nucleus for transcription; then mRNA translated in cytoplasm

 Early mRNA: products used to help with transcription, etc.

 Late mRNA: products for structural organization, assembly, etc.

Problems for viruses to overcome

1. Package info for replication into small genome
o Big variety of sizes of genomes
o Strategies: overlapping reading frames, code from both strands, splice RNA, frame-shift, RNA editing

2. Maintain in population without dying out

o Transmission
 Humans: respiratory/salivary, fecal-oral, or sexual contact
 Animals: vector (arthropod), vertebrate reservoir, vector+vertebrate reservoir
o Types of infection: acute, persistent, latent, relapsing
o Persistence: can’t kill host, kill cells in which virus replicates, or be eliminated by immune response

3. Need both stability (transmission) and instability (infection)

o Entry & uncoating strategies
 Endocytosis: both enveloped/non-enveloped,use clathrin-coated pits, enter cytoplasm; fuse
with endosome with acidification (often needed for viral protein conf. changes)
 Fusion: enveloped only, fuse directly with cell
Cytopathic effects:
membrane, discharge virus into cytoplasm
o Outcomes of infection  Rounding / swelling
1. Lysis  lysis
2. Transformation (e.g. pre-neoplastic)  syncytia formation (fusion, esp.
3. No pathological effects enveloped viruses)
 Chronic dysfunction can still result  hemadsorption (absorption on RBC)

Pathogenesis of viral infection

Disease : can be at site of entry (e.g. HSV) or at distant target organs(Coxsackie virus, enters via GI tract  myocarditis)
Time course of symptoms: due to local & systemic infection
 Local: earlier onset of Sx, due to infection of body surface (e.g. cold)
 Systemic: later onset of Sx, from immune response (e.g. measles)
 Rabies, hepatitis can be weeks, others are pretty short

Immune response
 Interferon:
1. dsRNA intermediate presence triggers Mϕ to synthesize & release IFN
2. IFN signals other cells via JAK-STAT pathway to induce antiviral protein genes (inhibit viral release /
products; ↑ MHC CLASS I EXPRESSION
3. Actually appears to control spread of virus before acquired immune response (acquired mops up,
allows for long-lasting immunity)
 Antiviral Antibodies:

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 1. Serological tests: Dx (ELISA, radioimmunoassay, Westerns)
2. Biological activity: function of Ab?
 Neutralizing (can’t cause productive infection). Effective immune response
1. Eliminate virus from blood/other
Can block attachment, endocytosis, uncoating.
 C’ fixation (causes cell death) fluids (prevent further spread)
 Hemagglutination inhibition (binds viruses 2. Eliminate virus-infected cells
together; can’t productively infect) from tissues (“cure infection”)
3. Roles of antibodies: protect against reinfection, clear 3. Immunity to re-infection
virus from fluids, downregulate intracellular virus replication (not completely understood)
 MHC Class I:
1. Mouse experiment: cytotoxic t-cells only kill MHC-I matched virus-infected target cells
 Cell-mediated immunity: focus immune response (target), clear infected cells, recruit other effector cells,
activate Mϕ , provide help for production of Ab by B cells

Basic immune response scheme:

1. Virus enters
2. Mϕ are 1st responders, pick it up
3. If dsRNA: IFN made
a. T-helpers activated to recruit B cells, Ab made against Mϕ and other infected cells
b. ↑ Mϕ activation (more MHC class I, etc.)
4. Infection cleared
a. T-suppressor cells help tone down immune response
b. Memory B-cells produced (longer-lasting immunity)

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 (+) RNA Viruses
Picornaviruses
Picornaviruses: Pico (small) RNA Viruses
 Icosahedral Human picornaviruses
 Receptor binds into canyon; neutralizing antibodies bind canyon too  Rhinoviruses
 Entry: endocytosis uncoating  conformational change in acidified  “Enteroviruses”
endosome  extrusion of RNA into cytoplasm (injected) o Polioviruses
 Plus-strand viruses: produce (-) strand intermediate in cytoplasm of cell o ECHO viruses
 Replication: (+) RNA translated as single polyprotein; viral proteases o Enteroviruses 68-71
cleave into individual proteins o Coxsackie viruses A&B
 Translation: have internal ribosomal entry site (IRES) in 5’UTR of RNA  Hepatitis A virus
o IRES: RNA can bind directly to ribosome w/o 5’ 7-methyl cap or
cap-binding protein

Clinical presentation
 Rhinoviruses: cause local upper respiratory disease (stay in resp. tract)
o Generally pediatric problem and nuisance
o Exception: asthma patients
 Enteroviruses: systemic infection
o Fecal-oral transmission  GI tract  viremia (in blood)
o Can go to
o Skin (hand-foot-mouth disease): Rash: pustules on skin
o Muscle (echovirus, coxsackie A/B): myocarditis, pericarditis
o CNS: Brain (polio, coxsackie A&B), meninges (echo, polio, coxsackie)
 Example: paralytic sequelae of poliovirus: limb atrophy

Poliovirus
Transmission: fecal-oral (land runoff, sewage, solid waste landfills)

Pathogenesis: infects throat, feces, blood, CNS (major disease effects

 Replicates in motor neurons of spinal cord
 Poliomyelitis: inflammation, death of motor neurons
o Phrenic nerve involvement especially bad: needed iron lung to support respiration

 Can shut off host protein synthesis

o IRES allows viral mRNA to bind / assemble
o 2A is a viral protease that cleaves elements of cap-binding protein assembly (initiation factor)
o Cellular RNA production stops but viral mRNA is fine!
o Cell death results (very little replication of own proteins)
Clinical manifestations of
Epidemiology: poliovirus infection
 summertime (virus not good in the cold! Seasonality: NE > south, etc.)  90-95% asymptomatic
 age dependence: was early in developing countries, late in industrialized  4-8% flu-like symptoms
countries  1-2% major disease
History: Unclear why some people get
 epidemics started early 20 c. (more leisure time, more time in common
th severe dz, others asx: virus/host
factors?
swimming pools, etc.)
 early attempts to control: quarantine  vaccines

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Vaccines:
 Sabin’s live virus vaccine helped reduce polio SALK VACCINE SABIN VACCINE
incidence big-time; wild polio eradicated (inactivated) (live virus)
o Advantages: spread immunity via shedding, Use Currently in US Not used in US
mucosal immunity, etc. Revertants to wt? No Yes (rare)
 Problem: tendency to revert to virulence (rapid Administration Injected Sugar cube
emergence of mutations) Mucosal immunity? No Yes
o Vaccine-associated paralytic polio: couldn’t completely get rid of polio as a disease with Sabin’s vaccine
(all new polio cases due to live virus vaccine)
 Switched to Salk’s inactivated virus vaccine (no more revertants)

Current problems:
1. importation of polio from endemic to polio-free areas
2. circulation of virulent vaccine-derived/recombinant viruses
3. prolonged excretion of vaccine viruses by immunodeficient individuals (e.g. AIDS pts)

Togavirus (rubella & alphaviruses)

 enveloped, (+)-strand RNA, icosahedral virus
o 2 types: rubella virus & alphaviruses
 Genome: RNA
o Genome is mRNA for nonstructural proteins (needed to synthesize RNA)
o Second subgenomic RNA is synthesized from part of genome for translation of structural proteins

Rubella
Respiratory transmission, worldwide distribution

Clinical presentation:
 Children / adults: mild maculopapular rash
 Congenital rubella syndrome (CRS):
o requires: maternal exposure, maternal blood invasion, placental Features of CRS:
infection, entry to baby’s blood, fetal infection 1. mental retardation
 lack of any of these means the baby will be healthy. 2. heart defects
o Don’t see CRS if mom gets rubella after 17-18 wks gestation 3. cataracts

Arbovirus encephalitis (caused by alphaviruses & flaviviruses)

Examples: alphaviruses, eastern equine encephalitis, western equine encephalitis

Remember: encephalitis occurs in a minority of cases (most flu-like if even have Sx)

Flaviviruses
 Mosquito-borne viruses (yellow fever, dengue, Japanese encephalitis, West Nile)
 Tick-borne viruses
 Hepatitis C too!

Transmission: birds are animal reservoir; humans infected incidentally via mosquito
West nile virus: spread really fast
 appeared in 1999, across USA over 5 years, caused lots of human disease
 now seems like more American birds have acquired immunity, human cases more sporadic

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 Coronaviruses
 (+)-strand RNA virus, transcribed and then translated
o Uses subgenomic RNA (along with genomic RNA) as mRNA, like togaviruses
 Morphology: looks like a crown
 Cause common cold and severe acute respiratory syndrome (SARS), which has pretty much disappeared

Summary of (+)-strand RNA viruses

Transmission Presentation
Picornaviruses Human (resp, fecal/oral) Variety: colds, polio, rashes
Togaviruses Human (resp) for rubella Rash, CRS
Mosquitos for alphaviruses encephalitis
Flaviviruses Mosquitos/ticks Fever, encephalitis
Coronaviruses Humans, ?animal for SARS Colds, SARS

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 HIV (and retroviruses)
History
AIDS: originally described as opportunistic infections in young adults: PCP pneumonia / oral candidiasis (1981)
Thought to be transmissible (epidemiology, hemophiliacs, epidemic in NYC & SF); HIV-1 discovered in 1983
 HIV-1: 3 groups, from SIV (simian), cross-species transmission responsible (SIV doesn’t often cause disease in
natural hosts but does in humans  animal model, use Asian macaques, which aren’t usual host  causes dz)
o M group causing AIDS epidemic currently
o (33M+ living with AIDS, 2.7M new each year, 2.0M deaths each year)
 HIV-2: SIV from West Africa, more slowly progressive, not as widespread as HIV-1

Found RNA-containing virus with reverse transcriptase activity; retrovirus morphology by EM

 immunologically distinct from human T-cell leukemia virus, only other significant retrovirus in humans
 much more like lentivirus (slow disease)
 Can’t really fulfill Koch’s postulates (hemophiliacs kind of?)  can’t put back into humans

Retroviruses
Enveloped, small genome (10kb), (+) ssRNA
 ssRNA capped, polyadenylated like host mRNA Retrovirus genes:
 Has reverse transcriptase & can integrate into host cell genome  gag: structural proteins
 RNA virus benefit: high mutation rate; DNA virus benefit: latent form in  pol: enzymes (protease,
host genome RT, integrase)
 env: coat protein
Complex viruses (also have accessory genes – regulatory gene expression)

HIV Structure
 gp120: surface glycoprotein, trimers, mediates interaction between virus & cell receptor
o Target of neutralizing & cytotoxic AB
 gp41: transmembrane glycoprotein: causes fusion of cell membrane, anchors gp120
 Core:
o 2 copies of viral RNA (needed for the RT step
o Protease, integrase, reverse transcriptase already packaged inside
Cell targets of HIV
CD4+ lymphocytes are targeted and killed by HIV
 Lose CD4+ lymphocytes in: peripheral blood, lymphoid/gut-associated lymphoid tissues
o (normal: 46%, decreased to 3%, etc). CD8 stays the same, so CD8/CD4 ratio increases
 CD4 < 200 is AIDS-defining (normal > 1000); blood level gives good indication of whole compartment
o Onset of opportunistic infections
 Normal jobs: Central in immune response (all arms)
o Mature in thymus into blood
o Recognize antigenic peptides (MHC class II), activate Mϕ, activate B-cells to produce antibodies

HIV also infects CD4+ monocytes/macrophages

 CD4+ monocytes in blood, bone-marrow-derived, migrate into tissues and take virus with them (brain, etc)
o Spread all over body in first few weeks of infection
 Normal jobs: antigen presentation, host defense, repair  differentiate into Mϕ
 Express MHC Class II molecules; chemokine receptors (CCR5/CCR2)

Natural History
 Initial viremia (virus up, CD4 down)
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  Innate, adaptive immune can control at first, CD4 rebounds but not to normal
 Virus keeps replicating (lymphoid tissues, dumped into blood), goes to set point (for longer period of time)
o The lower the set point, the better the prognosis
(immune system doing better)
o Therapy: keep viral load low

HIV Life cycle

Note: targets for antiretrovirals (except gene expression)
1. Attachment-fusion
a. CD4 (host) and gp120 (virus) interact; CD4 gp120
conf change
b. gp120 (virus) can then interact with CCR5 or CXCR4
chemokine receptor (host) (CD4 not sufficient)
i. CCR5-tropic HIV: on Mϕ (and T-cells
too)(primary infection, most infection)
ii. CXCR4-tropic HIV: T-cells only express
iii. Tropism can shift (R4 is much more pathogenic & cytolytic)
c. Conformational change of gp41 after chemokine
receptor/gp120 interaction Summary of HIV Life Cycle
d. gp41 mediates fusion of membranes & viral entry (core: 1. Attachment-fusion
RT, genome, etc) 2. Reverse transcription (RNA  DNA)
i. some viral particles still left on cell 3. Integration of viral DNA
4. Virus gene expression
2. Reverse transcription (RNA  DNA) 5. Assembly & budding
a. Very complex process 6. Maturation
b. Primer (tRNA from cell) bind primer binding site of viral
RNA in virion (near 5’ end)
c. RT uses primer to start making (-) DNA from RNA (RNADNA)
d. Rapidly runs out of RNA: goes to 5’ end of RNA, then jumps to either 3’ end of RNA or to the second
copy of RNA
e. Duplication results in DNA copy with LTRs (long-terminal repeats) on each end:
i. Allows you to transcribe another RNA without loss of genetic material
f. RNase H chews up the RNA as you go along (no editing capacity)
i. Higher mutation rate than in normal DNA replication

3. Integration of viral DNA

a. Random cut into non-histone coated DNA (endonucleolytic, sticky ends)
b. Insert viral genome
c. Host proteins repair the cuts: looks the same!
d. Until cell dies, can’t clear! – can sit here latently, carry to other parts of body, etc. (e.g. monocytes)
e. Latent virus is a reservoir

4. Virus gene expression

a. Activation state of cell determines either latency or productive replication (e.g. activated T-cell,
maturation of monocyte to Mϕ, etc. triggers replication)
b. Cellular transcription factors; cellular RNA pol II complex used to transcribe HIV DNA
i. Note switch to cellular machinery now (before was viral RT) – not drug targets!
ii. Cellular transcription factors, RNA pol II and HIV’s Tat assemble to achieve high levels of HIV
DNA transcription
iii. TAT also turns on some genes that are toxic to cell (would be good target)
c. Long terminal repeat is a cellular promoter region
d. Full length mRNA produced (whole viral genome), spliced (host cell proteins)
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 e. Translated to make structural proteins (full length mRNAGag polyprotein) and a longer protein (via
read-through of Gag’s stop protein to make Gag-pro-pol polyprotein, encoding protease/enzymatic
activity)
f. Cleaved via protease (viral)

5. Assembly & budding

a. Structural proteins (gag, gag-pol) myristolated (targeted for cell membrane), RNA targeted to nuclear
capsid & associates, then budding of the whole complex happens
b. This forms an immature virion which is non-infectious

6. Maturation
a. Protease gets bundled along; cleaves itself out of Gag-pol precursor protein
b. After budding: cleaves gag & gag-pol to form mature virion (infectious)
c. Maturation is essential to be infectious  PROTEASE INHIBITOR TARGET

Pathogenesis
Not that virus itself kills all CD4 cells: 2 accepted theories
 Immune activation: so much activation of immune system  exhausted (high level of activation)
 Bystander killing: activated T-cells more prone to apoptosis (more dying)

Transmission
Not a tough virus: fragile (not on surfaces, aerosol, etc)
 Sexual transmission (incl oral)
 Contaminated needles (IV drug use mainly; P=0.3% for needle stick, use antiretroviral PEP, call 5-STIX)
 Mother-child (in utero, at delivery, breastfeeding: all preventable with antiretroviral Rx)
 Probability of transmission depends on viral load (highest in acute infection & during AIDS)

Genetic polymorphisms: CCR5

 CCR5 is primary tropism for HIV transmitted sexually
 Some have 32 base pair deletions (Δ32/ Δ32) in CCR5 and are resistant to infection (1% Caucasians)

Spread:
1. Transmission  dendritic cells / infected Mϕ 
2. local LN  CD4 lymphocytes, Mϕ  viremia in blood 
3. spread to tissues  viremia in CSF (brain infected)
4. Long-lived reservoirs: resting lymphocytes (blood, tissues), Mϕ (tissues)

1st sign of infection: local LN involvement (make tons of viruses; viremia)

Stages of infection
1. Primary (acute) HIV infection: rapid replication (first few weeks),
a. Ab tests initially negative, viral load varies (104-106/mL), CD4 depletion (esp. GALT).
b. Acute retroviral syndrome: fever, lymphadenopathy, pharyngitis, rash
c. Viremia falls: innate, adaptive (CTL) immune response develops
d. Levels off to set point (different in different pts; prognostic)
e. LN full of virus; dendritic cells trapping virus inside LN, adaptive immune response clears
f. Viral load lowers, CD4 counts rebound

2. Asymptomatic (8-10 yrs usually, 20+ in long-term progressors)

a. Persistent infection, rise in viral load, decrease in CD4
b. Current guidelines: start Rx at CD4 > 350 (now being reconsidered)
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 i. Sooner is better for prognosis! Getting immune response the whole time (continual activation
of immune system, damage being done the whole time)
3. AIDS
a. CD4 < 200
b. Opportunistic infections (fungal, bacterial, parasitic, CNS, lungs, etc.)
c. Use prophylactic Rx to prevent opportunists

Treatment
Multiple drugs: mutation rate high (1 error/genome per 3 replication cycles)
 No editing function (single strand)
 “every base pair mutates every day”
 Partial suppression: rapid production of mutant viruses
 “Do it right or don’t do it”  sequential monotherapy = develop resistance to all!
o Never treat with one drug
o Never add 1 drug to a failing regimen
 3 drugs: likelihood of getting resistance to 3 drugs on same viral genome is low!

Latency & HAART

 Eradication was predicted (1st, 2nd phases showed you’d get done) – but latency was 3rd phase
 Latency: reversibly non-productive state of infection
o Resting CD4 T-cells & Mϕ in sites like CNS
o Normal T-cells: some activated T-cells return to resting state (1 in million) for ready response to future
infections, re-activate when activated
o Stable reservoir of latent cells throughout HAART (would need ~73 yrs to eliminate)

Vaccine?
 6 yr trial in Thailand: guarded possibility of vaccine? 30% reduction in those who receive vaccine; no reduction in
HIV load in vaccinees with HIV (?)
 Why so hard? All current viral vaccines prevent development of disease, don’t stop infection; HIV vaccine would
need to induce “sterilizing immunity” to prevent infection/latency; HIV infection doesn’t induce natural
immune response to prevent progression; would need vaccine against many variable clades of HIV-1/2, diverse
antigenicity among HIV in population

Tests for HIV

Serology: remember: HIV antibodies take 2-4wks to develop (can’t use right away!)
1. ELISA used as first test
ELISA + WESTERN PCR
o Pt. serum + HIV proteins in well; look for binding of
 Inexpensive  Expensive
pt. antibodies
 Rapid  Requires sample prep
o False-positive: 0.4%
2. Western Blot: Blood test (1985)  Requires Ab against  Detect early infection
o Used after ELISA to confirm (combined false- virus (2-4wks post- (3d post infection)
positive 0.005%) infection)  Can quantify viral load
o Purified virions lysed, run on SDS-PAGE Almost no difference in sensitivity
o Western-blot with patient sera to look for anti-HIV ab
RT-PCR
 Amplify RNA in virus (detects infection earlier: 1st week!)
 Gives you viral load: how much virus do you actually have in blood?
 CD4 and viral levels are most important clinical measures

Viral load, CD4 count (via flow cytometry) are the two best prognostic indicators
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 Small DNA Viruses: Parvoviruses & Papillomaviruses
DNA viruses: unlike RNA viruses, can use host cell nuclear enzymes to transcribe DNARNA & replicate DNADNA
Must either:
1. infect a dividing cell (parvoviruses)
2. induce host cell DNA synthesis (papillomaviruses, polyomaviruses, adenoviruses)

Parvoviruses
 Among smallest of DNA viruses; icosahedral virion (3 proteins + linear ssDNA, ~5000nt)
 Replicate in host cell nucleus
 Don’t have enough room to code for DNA synthesis enzymes: can only replicate in:
1. dividing cells that have necessary DNA synthesis enzymes
 autonomous parvoviruses can replicate alone
2. cells co-infected with a “helper” virus (that provides the enzymes)
 dependoviruses need a helper virus like adeno/herpes

PARVOVIRUSES THAT CAUSE HUMAN INFECTION: QUICK LOOK

Parvovirus B19 Autonomous Erythema infectiosum (“fifth disease”, childhood rash dz)
Acute/recurrent arthritis (adults)
Aplastic anemia/crisis (pts with chronic hemolytic anemia)
Chronic anemia (immunocomp / hydrops fetalis)
Bocavirus Autonomous Respiratory disease (infants)
Adeno-associated virus (AAV) Dependovirus No dz: gene vector (integrates into cellular DNA)

Virions: non-enveloped, icosahedral, linear + or – sense ssDNA, no enzymes, very resistant to inactivation

Genome: 2 reading frames

1. structural coat proteins (overlapping in-frame sequences) Parvoviruses
2. nonstructural proteins for transcription/DNA replication 1. Respiratory transmission 
2. Respiratory epithelium
Replication: nucleus 3. Viremia
1. cellular DNApol makes dsDNA  4. Skin, bone marrow
2. cellular RNApol makes mRNA (erythroblasts), fetus, GI tract
3. If autonomous: need host cell in S phase
a. (can’t stimulate S phase like papilloma viruses)
b. Predilection for bone marrow, GI tract, developing fetus (dividing cells!)

Parvovirus B19
Pathogenesis:
 B19 cellular receptor = globoside (P antigen), found
primarily on erythroid cells
 Virus replicates primarily in erythroid precursor cells
 Cytopathic effect: giant pronormoblasts with nuclear
inclusions, cytoplasmic vacuolization in bone marrow
 Toxicity: express B19 nonstructural protein (NSP) 
apoptosis induction
o Megakaryocytes: nonproductively infected
(no transcription of mRNA for structural
proteins) but NSP compromises & kills

Normal child/adult
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 0. 5-6d incubation
1. Viremic phase (108-1014/mL): fever, malaise, myalgias
2. “slapped face” rash (erythematous, strikingly flushed) afterwards ( immune response )
a. extends to extremities (lacy, evanescent, maculopapular)
b. Adults: develop arthritis during immune response

Destruction of erythroid precursors during acute phase  absence of reticulocytes in blood (transient mild anemia)
 Not clinically important usually, unless:

1. If patient has chronic hemolytic anemia (sickle cell, thalassemia, hereditary spherocytosis)
 More virus made & released (more bone marrow cells being produced & turned over more quickly)
 Already have shortened life for circulating erythrocytes, add on more anemia
 Result: APLASTIC CRISIS (“Transient Aplastic Crisis = TAC”, life threatening!)

2. If patient is immunodeficient:
 Can’t clear virus  chronic anemia (“pure red cell aplasia”)

3. If fetus
 Can cause severe anemia  hydrops fetalis (abnormal fluid in at least 2 compartments), infant death
 Greatest risk: first 2 trimesters,
 Treat: transfuse in utero, but baby might become tolerant to virus & have persistent infection / red cell aplasia

Epidemiology:
 Humans only (esp. school age kids & parents), respiratory transmission (also possible by transfusion)
 Dx: serology later, PCR during acute phase
 If immunocompetent: clear w/o tx, immunity is life-long
 Tx for immunocompromised: immune globulins; no vaccine

Papillomaviruses
HPVs: human papillomaviruses
 Icosahedral, covalently closed supercoiled circular dsDNA molecule, 8kb with histones (“minichromosome”)
 Cause warts & squamous carcinomas (e.g. cervical carcinoma)
 Culture: difficulty; typed via PCR usually

Replication: nucleus of squamous epithelial cells

 2 phases (overlapping reading frames on single strand)
o Early (E) genes: regulatory proteins for replication, transcription, transformation. E2,E6,E7 important
o Late (L) genes: capsid structural proteins (L1, L2)
o Long control region: origin of replication, control elements for transcription/replication

Disease/pathogenesis: species-specific, restricted tissue tropism

1. Cutaneous types: warts
o Virus enters skin via abrasion  basal layer of epidermis  express early genes
 E7: induces DNA synthesis
 Cellular proliferation (hyperplasia)  wart forms eventually
o As infected cells differentiate to keratinocytes, late genes expressed (L1/2), producing infectious virions
o Incubation period: months/years, crops of warts clear at same time (immune mechanism?)
2. Mucosal types: genital/oral/respiratory mucosa
o Worldwide issue
o Women: target proliferating cells at border of squamous/columnar epithelium of cervix
 Several months later: flat condyloma (asymptomatic)
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  Clearance of virus: 1-2 years, longer if HIV infected (↑ risk)
 Associated with ↑ cytologic abnormality in Pap smear
HPV & Cervical Carcinoma
Essentially all cervical carcinoma worldwide is initiated by HPV infection
 HPV-16, HPV-18 = MOST ONCOGENIC (70%)
 MORE RISK with longer persistent infection (e.g. HIV pts)

Oncogenicity: function of E6/E7 oncoproteins (both required for immortalization of keratinocytes)

 E7: induces DNA synthesis in resting cells (want basal cells to proliferate more)
o Binds retinoblastoma tumor suppressor pRB
 normally regulates growth by binding E2F, keeping G1/S checkpoint in check
 If RB bound by E7: E2F can go do its thing & release G1/S checkpoint (progress to S)
 E6: activates telomerase in epithelial cells; can complex with p53 in high-risk HPVs
o Targets p53 for ubiquitin-mediated degradation (no checkpoint control)
 E2: usually controls E6/7 expression
o HPV usually exists as unintegrated autonomously-replicating episome in nucleus
o In malignant cells: viral genome integrated in a way that disrupts E2 (cut circular genome in middle of
E2 to insert)  no control of E6/E7

Epidemiology:
 Common worldwide in men & women; also linked to penile squamous carcinoma, some head/neck tumors
 Most infected women are asymptomatic, clear infection, and do NOT develop malignant disease
 If developing disease
o Histopathologic progression: cervical intraepithelial neoplasia (CIN)  invasive disease
o Papanicolau smear: screening device; detects cellular changes
o PCR can be used to detect type
o Tx: removal of involved tissue

Immunization:
 Virus-like particles (VLPs) from L1 capsid protein (antigenically different between strains)
o Immunogenic: assemble into empty aggregate
 VLPs for HPVs 16, 18 (high-risk) & 6 ,8 (low risk, cause condyloma, prevent warts = good for marketing) in
current vaccine: prevents against both cancer & genital warts
 Possible therapeutic vaccine: E6/E7; for HPV-induced tumors

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 Influenza: Epidemics, Pandemics, and Prevention Strategies
Influenza quick review:
 wild waterfowl = natural reservoir; many strains circulate in birds
 influenza A & B = major cause of human disease (A is vast majority)
 Subtypes: classified by Hemagglutinin (H x 16), Neuraminidiase (N x 9)
o H1N1, H1N2, H3N2, novel (Swine) H1N1 circulating recently
 Mutations: antigenic drift (variations within same H&N classes) vs antigenic shift (complete H/N change)
o Shift: H, N, or both H & N: e.g. bird strain & human strain re-assort
 pigs are good facilitators (resp epithelium have both human-like & bird-like receptors)
 high association of shift with pandemics
 Pandemics of 20th c: 1918-19 (Spanish, H1N1, 20M dead Steps to cause an epidemic
worldwide), 1957-8 (asian, H2N2), 1968-9 (“hong kong”) 1. Susceptible population
2. Animalhuman transmission
Novel H1N1 3. Human  human transmission
 Very rapid progression, in viral spread & response (says good 4. Sustained humanhuman
things about current collaborative epidemiological efforts)
 Several steps removed phylogenetically from seasonal flu
 Now counting deaths instead of cases, expect combinations of infections with seasonal flu in winter
 Unusual features:
o Summer outbreak (seasonal=winter)
o High mortality in young adults without comorbidities (seasonal = elderly, infants, comorbidities)
 Symptoms = usually the same, just in young, healthy people too! 5-24yo unusually affected
 Asthma, COPD, CVD, diabetes, immunosuppresed seem to be important comorbidities

Seasonal influenza
 Annual epidemic spread like clockwork: late fall, winter, early spring (peak = Jan, Feb).
 All ages affected, highest rates among children, most serious in >65 and <2 years old + high risk conditions
 Annually 36k deaths, 226k hospitalizations in US; most deaths in >65yo
 50% peds deaths: no underlying high risk condition (secondary bacterial pneumonia is #1 cause)

Signs/symptoms: malaise, myalgias, headache, fever, non-productive cough, rhinitis, sore throat, otitis (peds)
 Normally a non-specific viral constellation; together = influenza-like illness (ILI)
 Uncomplicated: resolves in 3-7d with cough/malaise up to 2 wks (self-limited)

Complications
 Primary viral pneumonia
 Can exacerbate underlying medical diseases
 Secondary bacterial pneumonia / sinusitis / otitis
 Co-infection with viral/bacterial pathogens
 Uncommon: encephalopathy, transverse myelitis, myocarditis, pericarditis, Reye’s syndrome

Dx: difficult clinically to distinguish from other resp viruses; absence of ILI Sx doesn’t rule out flu
 Need lab Dx + high level of suspicion
 Lab dx:
o Nasopharyngeal aspirate: suction catheter, mucous trap, aspirate from posterior nasopharynx, add to
transport media, process < 1 hr
o Nasopharyngeal swab: have to get back to NP, better because won’t aerosolize (esp H1N1)
o After you get the sample: viral culture, immunofluorescente DFA antibody, RT-PCR, Serology

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Transmission of influenza
 Person-Person via large particle respiratory droplets, coughs/sneezes, 3 foot radius – can use surgical mask
 Close contact, contaminated surfaces
 Some evidence of airborne spread (small particle residue evaporated/suspended like TB – would indicate more
than just a surgical mask!)
 Observational studies in healthcare settings: contact/droplet are primary means; anecdotal airborne spread
 Incubation: 1-4d
o Adults: infectious from 1d prior to Sx through 5d post sx
o Children: infectious from several days prior to 10+d post sx
o Immunocompromised: can shed virus for months
o Shedding prior to Sx: more transmission (less precautions taken)

Vaccines
 Most effective way to prevent infection/complications
 Annually (antigenic drift)
 Two types
o Trivalent inactivate vaccine (TIV)
 Injected, grown in eggs, 3 strains (A/H3N2, A/H1N1, B)
 Inactivated/killed; subunit/subvirion/purified surface protein
 Cannot cause influenza (killed!) ACIP Recommendations
o Live, attenuated influenza vaccine (LAIV) for seasonal flu vaccine
 Intra—nasal administration; grown in eggs, 3 strains
 Children (6mo-19yr)
(A/H3N2, A/H1N1, B)
 Pregnant women
 Live attenuated virus; can cause mild signs / sx of
 >50yo
attenuated influenza
 Chronic med conditions
o Cold-adapted, LAIV (FluMist)
 2-50yo (FDA) and also 50-64; efficacy comparable to  Nursing homes / long-term
injected (85% healthy adults) care
 Well tolerated (rhinorrhea, nasal congestion)  Live with / care for high risk
 Don’t give to pregnant/immunosuppressed for complications
 Safe in healthcare setting (shedding short duration,  Healthcare personnel
less than dose to vaccinate, doesn’t replicate well at  Household contacts of
37F, genotypically stable, etc.) persons of high risk for
 Efficacy: prevention of illness among vaccinated subjects in complications; out of home
controlled trials caregivers of children < 6mo
 Effectiveness: prevelance of illness among vaccinated populations
o Depends on age, immunocompetence, match between ACIP Recommendations
vaccine/strains, outcome measured (death, hosp., etc) for H1N1 flu vaccine
o Good (80-87% kids, 77-90% working adults, less in elderly in  Pregnant women
community / long-term-care)  Household contacts of
persons of high risk for
Medical conditions with ↑ risk of complications complications; out of home
 COPD + asthma caregivers of children < 6mo
 CVD (not HTN)  Healthcare / EMS
 Renal, hepatic, hematological, metabolic disorders (incl. DM)  6mo – 24yo (ALL)
 Immunosuppresion (meds/disease like HIV)  25-64 with higher risk
 Cognitive/neuro dysfunction that compromises resp function or conditions
increases risk of aspiration
*note: no prioritization of
elderly!
Hard to make vaccine: WHO decides in feb which strains to include; 6-8 mo

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of production, 10s of millions of hand-picked 11-day-old chicken eggs to inject with strain, incubate for several days,
extract/purify egg white: LABORIOUS
Vaccination “season”: people stop getting vaccinated after Thanksgiving although most influenza is in Jan/Feb
 Need to keep up vaccination efforts!

Influenza in health care workers: common (23%, most can’t remember flu or resp symptoms)
 Vaccinate: ↓ patient mortality, ↓ lost hours, ↑ normal function of institution in flu season
 Doesn’t make you sick (large double-blind placebo study)

Antiviral meds: adjunct to vaccination, not substitute

 Adamantanes (amantadine, rimantadine)
o Single point mutation confers resistance; was common in H3N2 circulating strains, was recommended
against for a while, now active against H1N1?
 Neurominidase inhibitors (oseltamivir, zanamivir)
o Resistance mostly in seasonal influenza, increasing over last few seasons
o Active against flu A & B; 83-4% active for prevention, bad in pregnancy?
o Can use for chemoprophylaxis
 NOT vaccine substitute; adjunct
 ~85% effective in household exposure, use in institutional settings (prevent spread in
outbreak), protect high risk when flu circulating (vaccine takes 2 wks to make Abs), protect
immunocompromised, protect those with contraindication for vccine
 Can use for therapy or prophylaxis, both have similar effects in decreasing length of illness

Other prevention
 Hand-washing, respiratory etiquette, community mitigation (close schools, avoid mass gatherings wear masks)
 Respiratory etiquette:
o Cover nose/mouth, use tissues, use hand-hygiene after resp secretions / contaminated objects,
healthcare facilities need to make tissues / hand sanitizer available in waiting rooms!
o Provide no-touch receptacles, tissues; dispensers of alcohol, use masking/separation if resp. symptoms
o Droplet precautions: use mask if sx of resp infection, esp in setting of fever

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 Viral gastroenteritis
Some viruses replicate in GI tract but don’t cause GI disease: (Enteroviruses: polio, coxsackie, echo, HAV, reoviruses, adenoviruses)

To infect GI tract: need resistance to low pH, detergents (bile), proteases (small intestine)
 Some viruses even co-opt these features as part of life cycle!
Review: anatomy of small intestine
Some viruses replicate in GI tract and cause gastroenteritis  Crypt cells (dividing, secretory)
 Norovirus: (+) RNA no envelope  Villus cells (tip = mature, non-dividing, absorptive)
 Rotavirus: segmented dsRNA no envelope  M-cells (Peyer’s patches, like LNs)

Pathogenesis of viral gastroenteritis: Different viruses infect different sites in small intestine
ingestion  mucosal infection  diarrhea  more transmission

Rotavirus
Rotavirus diarrhea: most common cause of severe dehydrating diarrhea in young children

Rotavirus: segmented, dsRNA (1 segment = 1 protein), no envelope

 In Reovirus family
 RNA alone not infectious
 Different segments = different viruses; can distinvirionguish rotaviruses based on electrophoresis
o Can reassort during dual infection of cells
Structure
 Outer capsid: VP4, VP7 (role: attachment & entry; neutralization / protective immunity target)
o VP7: viral surface glycoprotein, major part of virion
o VP4: much smaller component
 Trypsins from small intestine: cleave VP4  VP8* + VP5*
 Required for infectivity: once cleaved, can exposes fusion domain & allows fusion/entry
 VP5* selectively permeabilizes membranes
 Core:dsRNA genome woven into capsule structure on inside

Steps in infection:
1. Ingest virion  to small intestine  trypsin cleaves VP4  entry mediated
2. Intermediate sub-viral particle formed (ISVP)  enters lysosome, cytoplasm, etc.
 STAYS as ISVP (intact) – doesn’t fully uncoat like other viruses to show genome
3. ISVP has its own VIRAL RNApol – makes (+)-strand RNA & extrudes into cell
4. New RNA can be used as mRNA to make proteins, assemble virus, etc.

Cypopathic effects:
 see blunted, vacuolated villi
 MATURE enterocytes infected, not dividing cells at base of crypts
o In one week: everything restored (more being made at base, infected cells turned over)

Pathogenesis:
 If you have neutralizing antibodies (anti-VP4/7), halts infection (VACCINE target)
 Rotavirus infects mature absorptive enterocytes in small intestine; produce & release NSP4
o Cellular disruption leads to ↑Ca+2  malabsorption & osmotic diarrhea
 Productive infection  production of NSP4: viral enterotoxin
 NSP4:
1. Stimulates Cl- secretion from crypt cells (causes osmotic diarrhea)

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 2. May also stimulate enteric nervous system (more diarrhea)
Diarrhea: good for virus: more transmission Rotavirus Dx
 Often hard to
Clinical features: (vs other virus causes): high prevalence of vomiting & dehydration culture viruses
 Esp. important in infants – can’t tolerate huge volume depletion  Use antigen-
specific enzyme
Epidemiology: immunoassay
 younger kids (6mo-1yr) get more rotavirus gastroenteritis, diarrhea (stool specimen)
 Biggest single cause of infant diarrhea in both developing & developed countries
o (US: million cases/yr, 150 deaths, $350M in costs; developing countries: 150M cases, 900K deaths/yr)
 Seasonality: more in winter (opposite of enteroviruses)

Vaccine: made by reassortants (rhesus monkey/bovine + human – less virulent but still antigenic)
 One was pulled (linked to intussusception – one part of bowel slides into another like telescope – in infants) in
1999 (rare cases)
 Two live, oral, attenuated vaccines are FDA approved now (bovine reassortment, no intussusception risk)
o Now routine in US

Norovirus
Outbreak of gastroenteritis (1972, Norwalk, OH) – “winter vomiting disease” but no true seasonality
Found viral source: related to small rounded structure viruses; all termed Calciviruses

Norovirus:
 (+) ssRNA, no envelope
 Cup-shaped indentations on surface (β-parallel sheets)
 Only infects some people: depends on receptor status in host & blood type
o FUT2 encodes a carbohydrate that’s part of receptor
o If receptor present: “secretor” (secretor ≫ non-secretor for susceptibility)
o O > A/B for susceptibility (blood types)

Clinical features: high level of variability (some vomit w/o diarrhea, others vice-versa, some both)
 Delayed gastric emptying might be involved (asx infected = no delay)

Epidemiology: all ages, all groups, across the board

 (% with serum Ab increases with age, esp. post 6yrs, depends on country)
 Acute gastroenteritis outbreaks (e.g. banquets,day care, cruise ships, nursing homes, etc.)
o Most common etiology of foodborne illness outbreaks (& foodborne illness overall!)
o Easy to spread (hand-hand, surfaces, etc.)
o Also: wells, water supply, nursing
homes/hospitals, etc. SUMMARY OF GASTROENTERITIS VIRUSES

Infectivity: stool, vomit are infectious Rotavirus

 Many strains with little durable immunity  dsRNA virus that synthesizes RNA inside a
transcriptionally active particle
Dx: no routine tests (usually just for investigations)  Most common cause of dehydrating diarrhea in
Rx: supportive (usually self-limiting 2-3d) children <2yo worldwide

Calicivirus (e.g. Norovirus)

 (+) ssRNA virus with genome similar to
picornaviruses
 Outbreaks of gastroenteritis in all ages
 Most common cause of infectious GI illness
(food-borne, cruise ships, water-related, etc).
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 Gammaherpesviruses: EBV / KSHV
Epstein-Barr Virus (EBV)
 dsDNA, large genome
 Immortalized B-cells: after infection with EBV: enter cell cycle, proliferate, grow indefinitely in tissue culture,
tumorigenic in mouse models

Epidemiology:
 Everybody, everywhere (>95% adults worldwide)
 Primary infection: transmitted in saliva
o Asymptomatic if infected as a kid (most exposed in early childhood)
o Infectious mononucleosis if infected later in life (25-70% of adults infected develop Sx)
 Most important diseases are associated with latency (tumors) – very uncommon

Virology:
 Has a lytic and a latent phase of infection (Burkitt’s cells are slightly different because they have less protein
expression and are therefore less immunogenic)
o Lytic phase: spread via infectious virions like normal virus
o Latent phase: hangs out in epitopes
Lytic infection of B-cells Latent infection of B-cells Burkitt’s B-cells
(“immortalized”)
Genome Linear Circular epitopes
Viral (acyclovir susceptible), Host (not acyclovir susceptible)
DNApol used
Viral enzymes expressed Viral enzymes not expressed
Lots of proteins expressed Lots (antigenic) Only one (invisible to CD8+
Gene expression T-cells because of lack of
MHC-1 presentation)
Immune response Big response Big T-cell response No T-cell response
Infectious virions Host cellular proliferation; no virions made
Spread
(epitopes partitioneddaughter cells when replicating)

Keeping virus under control:

 T and NK Cell response (atypical lymphocytosis)
o Kills many infected B-cells
o > 1% T cells in most seropositive healthy people target EBV (huge response, surveillance)
o T cells rapidly kill off immortalized B-cells, not Burkitt’s cells

Infectious Mononucleosis
 Especially prevalent if primary EBV infection occurs as adult
Pathogenesis
1. Transmission: Saliva (“kissing disease”)
2. Immortalization of lymphocytes in vivo
3. T cell response, most immortalized B-cells are killed
4. A small number of EBV-infected resting B-cells have minimal antigen expression (like Burkitt’s cells)  escape
5. Reactivation of these infected, resting B-cells occurs sporadically (unknown why)
6. Intermittent in everyone (reactivation): Production of virus, shedding in saliva, infectivity
Clinical features
 Sore throat, fever, generalized lymphadenopathy (esp. cervical)
 Atypical lymphocytosis (activated T & NK cells): “ mononucleosis” is really a lymphocytosis
Diagnosis
 (+) heterophilic monophile test
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 o Turns out that Abs generated during infectious mononucleosis will agglutinate horse RBCs (weird &
accidental cross-rxn)
o “ Monospot” test used currently based on this
o Disappears with resolution of acute illness
 Serology: IgM to viral capsid antigen (VCA) for current infection; IgG for post-infection

Burkitt’s Lymphoma
 Young males, maxillary / periorbital tumor
EBV Tumor associations
 Equitorial Africa only (malarial distribution): not high
Lymphomas Other
altitudes or deserts
Endemic Burkitt’s Nasopharyngeal carcinoma
 Escape immune detection (makes few viral proteins) B-cell in immunodeficient Gastric carcinoma
 Exact EBV – BL relationship unknown Hodgkin’s disease

B-cell lymphoma (immunodeficient pts)

Basic idea:
 T-cells suppressed, pretty much everybody has EBV B-cells
 can’t keep them in check anymore and end up with B-cell lymphoma (uncontrolled growth)

Patients:
 Transplant patients on cyclosporine, etc – if stop suppression, tumor regresses
 Severe combined immunodeficiency (SCID), X-linked immunodeficiency: often die of EBV B-cell lymphoma
 AIDS lymphoma: 50% increased risk
 (X-linked agammaglobulinemia, XLA): no risk (no B-cells = no EBV, no B-cell lymphoma)

Hodgkin’s lymphoma
 EBV in tumor cells in 30% of cases (associated)
o Find EBV DNA/RNA/Ag at each tumor site, during presentation & during relapse

Nasopharyngeal carcinoma
 Especially prevalent in Southern China (genetic & environmental)
 Virtually ALWAYS EBV-associated (not well understood)

Kaposi’s Sarcoma Herpesvirus (KSHV)

KSHV
 Unlike EBV, doesn’t infect most people (rare except in HIV, MSM, special pops)
 Found via PCR in B-cells of seropositive individuals, DOESN’T IMMORTALIZE like EBV
 Several genes closely mimic human genes (e.g. viral IL-6)
 Transmission: early childhood in endemic regions (saliva?), ? sexual trans in MSM? Rare in transfusion, IV

Kaposi’s sarcoma
 KHSV infection is required
 Geographic: Children in Africa (hands/legs); old men in Mediterranean (Italy, Greece, etc.),
 Immunosuppresion:
o Organ transplant recipients (regress with withdrawal of immunosuppresion
o AIDS patients: especially MSM in North America & Western Europe
 Presentation: tumor, most commonly on skin, may also be GI/lungs
o Neovascular proliferation  purplish color

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 Primary Effusion Lymphoma
 In AIDS patients, B-cells float in pleural/peritoneal fluid (no solid component)
 Exceedingly rare
 Pts DUALLY INFECTED (EBV+KSHV)

Main Concepts (review)

Latent infection:
 How can a virus establish latency in a dividing cell? How can a virus spread inside a host while latent?
o Need to be able to make DNA that can go into daughter cells
o EBV/KSHV have episomes that are replicated using host machinery & partitioned to daughter cells
 Are viral genes expressed in latency?
o Yes: can be one, a few, many – and virus can take over cell, make it grow out of control
 Can disease processes be associated with latent infections?
o Yes: tumors for example
Lytic infection/reactivation GAMMAHERPESVIRUS TUMOR ASSOCIATIONS
 Is it always harmful to the host? Nasopharyngeal carcinoma
Always EBV associated, regardless
o Not usually – don’t usually want to of geography
measure EBV in blood (diseases aren’t EBV associated in malarial areas of
Burkitt’s lymphoma Africa but not in North
virions but are latent virus)
America/Europe
Tumor associations Hodgkin’s lymphoma Sometimes EBV associated
 What does tumor association mean? Kaposi’s sarcoma Always KHSV associated
o Not just that colon cancer has EBV – Primary effusion lymphoma KSHV and EBV associated
everybody is EBV positive!
o Need to find virus in cancer cells

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 Viral Hepatitis
Hepatitis = inflammation in the liver
 Nonspecific: alcohol use, acetaminophen, etc. can cause too
 Infectious causes: nonviral (syphilis, TB, histo, etc.) and viral (CMV, EBV, HIV, H[A-C]V, etc.)

Hepatitis viruses: Certain viruses only cause hepatitis clinically

 A to E, really a clinical grouping, not biological (some DNA, some RNA, etc.)

Clinical course of Hepatitis: exposure  incubation (3-4wks)  symptoms (jaundice)  recovery or persistence
 Acute viral hepatitis (USA): A>B>C for frequency
 Chronic viral hepatitis: B & C (A can’t cause chronic hepatitis)

Transmission:
 A (& E) is nonenveloped, not killed by bile, so can be Exposure HAV & HEV HBV & HDV HCV
transmitted fecal-oral (acute) Fecal-oral +4 0 0
 Note that the chronic ones can be transmitted via blood Sexual +1 +4 +1
(makes sense) Blood +1 +4 +4
 Sexual: oral or vaginal Perinatal +1 +4 +2

Clinical features of acute viral hepatitis

 HAV+HEV: provokes a stronger immune response than B/D, C
o Shorter incubation HAV+HEV HBV+HDV HCV
o Higher % with jaundice Incubation (weeks) 2-6 6-24 6-300
o No persistence % Jaundice 30-70 20-40 15-25
 HCV: big one for persistence % Persist 0 5 80

Consequences:
 Liver: largest organ in body, stores vitamins A, B12, D, E, K; metabolizes lipids, makes cholesterol, stores
glycogen
 Fibrosis: scarring (overgrowth of connective tissue), restricts function  bridging (bands of fibrosis)
o Cirrhosis: widespread fibrosis with nodule formation macronodular cirrhosis
 Hepatocellular carcinoma (primary cancer of the liver; one of most common in world, cirrhosis is risk)

Lab Dx:
 Elevated transaminases (ALT, AST > 10x normal): liver-specific enzymes, spilled out in ongoing damage
 Antibodies
o IgM antibodies: markers of recent infection (6 mo)
o IgG: markers of any past infection
o Neutralizing Ab: recovery process under way
 Viral particles(protein/nucleic acid, “antigen”): ongoing infection and infectivity

Prevention: Vaccines (HAV, HBV) or immunoglobulin administration (HAV, HBV)

Treatment: none for acute hepatitis; there are treatments for chronic HBV/HCV

Hepatitis A virus
 Picornavirus, RNA virus
 NO ENVELOPE  bile stable (can be transmitted fecal-oral)
 Capsid proteins elicit a universal neutralizing antibody (one serotype  vaccine possible)

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 Hepatitis B virus
 S-gene: surface antigen, makes surface antigen in outer envelope;
o first recombinant vaccine (yeast) produced against it (1st anti-cancer vaccine)
 Genome: tiny (3200nt), uses overlapping reading frames
 Replication: entry  uncoating  genome incompletely closed (opened from circle) to be imported to nucleus
o Completly Closed Circular DNA (cccDNA): genome closed & repaired inside nucleus
 Makes a bunch of transcript for viral replication
 Can be INTEGRATED into host genome (stable, reservoir) – hard to eliminate
 Transmission: makes TONS of virus and extra surface antigens (serum packed); environmentally stable (can
hang out on tables, equipment, etc). Very transmissible

Hepatitis D virus
 Has Dependency issues: needs Hepatitis B (either via co-infection or prior chronic infection)
o Uses HBV to put on its capsule (has HbsAg) but has its own RNA

Hepatitis C virus
 Tons of genomic diversity
o Error rate: 1x10-4; turnover is really high (1010-12 per day)
o Mutations: every base, every day, every person (like HIV)
 Forms quasispecies
 Even more genetic diversity than HIV
o Explains failure of vaccine & immune response to clear (some variants can evade & persist)
 Abs don’t neutralize (too much diversity)
 Steady progression of chronic disease, often cirrhosis  end-stage liver disease (ESLD)
 ALT at constant elevated rate; RNA present the whole time
 Clinical correlations of genetic diversity
o 80% persistence, resistance to treatment
o HCV is hard vaccine target, hard target for antiviral drugs
o Reservoir: infections last for decades

Hepatitis E
 40d average incubation; 1-3% CFR
 Pregnancy: often fulminant (15-25% CFR!)
 Higher severity with age; no chronic sequelae

Summary/Review

5 hepatotropic viruses
TRANSMISSION COURSE KEY FEATURE
HAV Fecal/oral Self-limited No envelope = bile stability
HBV Surface antigen in vaccine
HCV Blood/sex/etc Chronic Viral diversity
HDV Needs HBV
HEV Fecal/oral Self-limited Fatal in pregnant women

 Viral particles: ongoing infection

 Anti-viral Abs: IgMs are recent

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