Hepatitis C nonA, nonB, Hepatitis

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Hepatitis C ( non-A, non-B, Hepatitis)

• Hepacivirus Hepatitis Virus C
• Enveloped, positive-sense RNA
• Six major serotypes
• Clinical Progression
• Initially most patients are asymptomatic
  (subclinical)
• Only slight elevation of liver enzymes
• Some will experience anorexia, malaise, and
  abdominal pain
• Jaundice occurs in a small percentage of patients
• Pathologically the patient has chronic active
  hepatitis
• Incubation period 6-7 weeks seroconversion
  8-9 weeks
• This will ultimately progress to chronic liver
  disease
• 70-90 will develop chronic disease
• With time, many of these patients will develop
  cirrhosis
• 5-25 of these will develop hepatocellular
  carcinoma

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Hepatitis C Diagnosis and Epidemiology

• Diagnosis
• Serological detection of Anti-HVC antibodies
• Antibodies only indicate exposure, but do not
  stage the disease - EIA
• Antibodies titers tend to be low
• Nucleic acid detection
• Detects circulating HVC- RNA
• Uses RT-PCR methods converts viral RNA to DNA
• Epidemiology
• Reservoir humans throughout the world
• 170 million chronic carriers worldwide
• Transmission Person-to-Person, direct/indirect,
  blood-body fluids
• Most common cause of post-transfusion hepatitis
• Mortality
• 8000 10,000 death/year in U.S from end-stage
  liver disease
• High Risk Groups
• IV drug users, hemophiliacs, blood transfusion
  recipients, sex, health care workers

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BunyaViruses - Characteristics

• spherical, enveloped, negative sense, segmented,
  single-stranded RNA
• three strands of negative sense RNA
• two envelope glycoprteins no matrix protein
• genomes associated with the RNA dependent RNA
  polymerase ( L protein)
• replicated in the cytoplasm
• most are Arthropod Borne Viruses
• Clinical Diseases
• Hanatavirus Pulmonary Syndrome
• Hemorrhagic Fever
• California Encephalitis
• LaCrosse Encephalitis

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BunyaViruses Clinical Diseases

• Hantavirus Pulmomary Syndrome
• prodrome of fever and muscle aches followed by
  interstitial pulmonary edema, respiratory
  failure, and death
• Encephalitis
• sudden onset of fever, headache, lethargy,
  vomiting
• seizues occur in 50 of patients with
  encephalitis
• Hemorrhagic Fever
• petechial hemorrhage, ecchymosis, epistaxis,
  hematemesis, melena, bleed of the gums

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BunyaVirus Encephalities

• Symptoms classical encephalitis
• Acute onset of severe bifrontal headache and
  fever ( 38 -40C)
• Some vomiting, lethary, and convulsions
• Death from seizures lt 1 fatality rate
• CaliforniaEncephalitis Virus Complx
• LaCross Virus an Othobunyavirus
• Major cause of encephalitis and aseptic
  meningitis in children in the upper midwest
• Reservoir small mammals
• Squirrels, chipmunks, rabbits
• Transmission animal-to-human, indirect,
  arthropod-borne, mosquitoes
• Mostly Aedes triseriatus ( oviposits in tree
  holes)

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BunyaVirus Hemorrhagic Fevers

• Many in the world
• None in U.S.
• High Mortality

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HantaVirus Pulmonary Syndrome

• Etiological Agent
• HantaVirus Sin Nombre Virus ( a Bunyavirus)
• Symptoms
• Acute onset of fever, headache, and myalgia
• Followed by rapidly progressive pulmonary edema
• Patient dies from respiratory compromise
• No signs of hemorrhage
• Pathogenesis
• Virus infects the endothelial cells and
  macrophages of the lung, heart, spleen, and lymph
  nodes
• Essence of disease is functional impairment of
  vascular endothelium
• Epidemiology
• Reservoir deer mouse (Peromysus maniculatus)
• Transmission aersolized rodent excreta
  inhaled
• Disease is not common, but has a 30 mortality
  rate

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Retroviruses - Characteristics

• enveloped, positive sense, RNA viruses ( 80 -
  120nm)
• particles carry two identical copies of
  positive-stranded RNA
• genome is not infectious does not encode for a
  polymerase
• three genes which encode polyproteins
• gag group specific antigen on capsid
• pol polymerase, protease, integrase
• env envelope glycoproteins proteolytic
  cleavage of this polyprotein produces the
  individual envelope glcoproteins
• LTR sequences encode promotors and enhanaces
  assocatiaed with transcription
• envelope conatains two glycoproteins
• gp 41 and gp 120 both cleaved from the env
  polyprotein gp160
• gp 120 establishes tissue trophism and
  antigenicity also subject to antigenic drift
• gp 41 promotes cell - to - cell fusion

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RetroVirus - Characteristics

• cone-shaped core (Lentivirinae) carries several
  enzymes
• RNA dependent DNA polymerase (reverse
  transcriptase) 10 - 50 copies
• integrase promotes integration(recombination) of
  viral genone into cell DNA
• t-RNAs serve as primers for the action of
  reverse transcriptase
• the viral DNA copy becomes a cellular gene
  through integration into the host cells
  chromosomes
• Subfamilies of Retroviruses
• Oncornavirinae HTLV-1, HTLV-2
• Lentivirinae HIV -1, HIV -2

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RetroVirus Viral Cycle

• Adsorption
• gp 120 binds the virus to cells prossessing CD4
  receptors this establishes the tissue(cell)
  trophism
• T- helper cells
• macrophages, dentritic cells, and microglial
  cells
• accessory receptor (transmembrane G - protein)
  also defines the trophism
• Penetration
• the adsorption process brings the gp41 into
  contact with the host cell membrane which the
  promotes the fusion of the virus with the cell
• some retroviruses enter by endocytosis and do not
  untilize gp41

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RetroVirus Viral Cycle

• Transcription and Replication
• when genome is released into the cytoplasm, the
  t-RNA acts to facilitate the synthesis of a
  negative sense DNA through the action of reverse
  transcriptase
• the RT, then acts as a ribonuclease and digests
  the positive RNA strand
• then the negative sense DNA is used as the
  template for the positive sense complementary DNA
  strand double stranded DNA
• the DNA which results is circular DNA is longer
  than the original RNA
• double stranded cDNA is delivered to the nucleus
• DNA is then spliced into the host chromosome
  through the action of viral integrase once
  integrated the viral DNA is transcribed as a
  cellular gene
• using host cell DNA dependent RNA polymerase II
• replication of viral genome occurs via
  transcription of the integrated viral DNA to RNA
  replicas since virus acts as a cellular gene,
  this process depends upon the cells ability to
  read LTR and use the enhancer/promotors
• other products of this transcription include m
  -RNAs for the gag, pol, and env polyproteins

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RetroVirus Virus Cycle

• Accessory Gene Products
• tat/rev
• nef
• vif/vpu
• Assembly
• viral glycoproteins are cleaved from the
  polyproteins( gag, pol, env) glycosalated, and
  processed by the endoplasmic reticulum and Golgi
  then incorporated into the host cell membrane
• viral genome replicas, together with t-RNA, viral
  protease, and other enzyme products bind to the
  cell membrane in areas expressing the envelope
  glycoproteins
• Release
• the virus is released from the host cell via
  budding
• acquires its glycoprotein envelope
• once the virus exits the cell, it is not
  infectious until the viral protease carried in
  the particle cleaves the gag and gag-pol
  polyproteins this intraviral cleavage releases
  the reverse transcriptase and forms the virion
  core
• many anti-AIDS drugs target the viral protease

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RetroViruses

• Viral Pathogenesis/Cytopathology Fig 61-8
• virus primarily infects the CD 4 cells including
  the cells of macrophage lineage monocytes,
  macrophages, dendritic cells of skin, microglial
  cells
• the local tissue macrophage is the initial site
  of viral infection/replication
• this results in persistent low level productive
  infection with virus being shed into the blood
  and body fluids
• gt viral load with viremia mononucleosis-like
  symptoms
• monocytes and macrophages are persistently
  infected and continually seed virus into the
  circulation major reservoir for virus
  distribution
• initial CD 4 T-cell infection occurs in the lymph
  nodes
• lytic infection of T-cells
• synctia formation with cells expressing larges
  amounts of CD 4 antigen
• CD 4 and fusin chemokine receptors required to
  establish this phase
• some people lack chemokine receptors and are
  immune to AIDS
• genetic or constitutional immnity lt 2 of human
  population
• late disease involves lymph node changes, and
  death of CD 4 T-Cells
• this is immunosupresson with not T-cells (or T dh)

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RetroViruses - Pathogenesis

• Additional Points about HIV Cytopathology
• 1. Since cells of the monocyte-macrophage lineage
  circulate throughout the body, they play a
  significant role in the spread of the virus
• 2. HIV induces several cytopathic effects in CD 4
  T-cells which lead to their death.
• accumulation of circular non-integrated DNA,
  changes in cell membrane permeability, syncytia
  formation, and apoptosis(programed death)
• 3. Macrophages do not exhibit significant
  cytolysis because they express fewer CD 4
  receptors cytolysis occurs most readily in cells
  expressing the greatest amount of CD -4 receptors
• 4. expression of the nef protein is essential
  for the progression to the state called AIDS
• 5. CD 8 T-cells also play a role in the
  progression of AIDS

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Lentivirus Acquired Immunodeficiency

• Acquired Immunodeficiency Syndrome (AIDS) phases
  of AIDS
• asymptomatic - initially the viral load in low
  and infection occurs without symptoms
• symptoms of early infection may resemble
  influenza or mononucleosis
• lymphadenopathy may accompany or follow(persist)
  this stage
• asymptomatic with chronic lymadenopathy
• virus is replicating within the lymph nodes
  during this phase
• during this stage ARC may occur\
• lymphadenopathy with fever, weight loss, and
  malaise
• mild opportunistic infections, diarrhea, night
  sweat, fatigue
• gradually deterioration of the immune response
• indicated by repeated opportunistic infections
  (Table 61-5)
• such infection parallels the decline in CD 4
  T-cells to lt 450/dl
• complete immunosupression or full-blown AIDS
• occurs when T-cells decline to 200/dl or less
• virus load in high at this point high levels of
  virus and p24 in blood

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AIDS - Diagnosis

• Symptoms of Immunosuppression repeated
  opportunistic infections
• Laboratory Diagnosis Table 61-6
• Antigen detection detection of p24 viral
  antigen, reverse transcriptiase, or viral RNA is
  indicative of recent infection
• Serology detects presence of antibody against
  viral glycoprotein antigens ELISA, Western Blott
• serology does not detect early infection only
  after 6 - 8 weeks of infection does antibody
  appear
• Culture not routinely performed only
  epidemiologically important
• Epidemiology
• Reservoir
• Modes of Transmission
• Rick Groups
• Control
• Education
• Screening Table 61-6

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Deltaretrovirus Human Lymphotrophic Viruses

• Leukemia Viruses HTLV -1
• Acute T-cell lymphocytic leukemia in Adults (
  ATLL)
• Fatal within one year of diagnosis
• Neoplasia of the CD 4 (mature T-cells)
• long latency of 30 - 50 years
• not a cytolytic infection, but infected cells
  exhibit growth changes which are not associated
  with oncogenes
• malignant cells are pleomorphoric with biloulated
  nuclei flower cells
• elevated WBC with lymphocytosis ( T- cells) and
  skin lesions
• transmitted by person -to - person, blood and
  blood fluids
• direct sexual,
• blood transfusion, IV. Drugs, etc.

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Hepatitis Viruses

• Classsification
• Picornavirus Hepatitis Virus A
• Hepatitis Virus A
• Short Incubation Hepatitis 15 -60 days (avg 30
  days)
• Unlike on picornaviruses, HVA is not cytolytic
  and is released by exoctyosis
• HVA adsorbs to receptors on liver cells
  (heptacytes) and Kupffers cells
• No apparent cytopathological effects persistent
  infection
• Liver pathology is due to the action of natural
  killer cells and cytotoxic T-cells which lyse the
  virally infected cells
• Jaundice usually accompanies the appearance of
  virus specific antibody
• Immunity due to virus specific antibody is life
  long
• Flavivirus Hepatitis Virus C
• Hepatitis Virus C
• Incubation period of 14 -180 day(avg 7 - 21 days)
• Basis for 90 of NANB hepatitis
• Generally establishes persistent, non-lytic
  infection, leading to chronic disease
• Transmitted parenterally(transfusion) and sexually

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Coronaviruses - Characteristics

• Classification
• Positive sense RNA
• Encodes a RNA dependent RNA polymerase (L)
• Enveloped
• Glycoproteins E2 functions a both VAP and fusion
  protein
• Other glycoproteins

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Coronaviruses - Diseases

• Acute rhinitis
• Common cold second most common cause of acute
  rhinitis 15-20 of cases
• Replicates best in cell of the upper respiratory
  tract which function at 33-35 C
• Viral Cycle
• Typical positive sense RNA,enveloped virus cycle
  except that the positive sense RNA buds into the
  Endoplasmic Reticulum, acquires it envelope, and
  is released from the cell by exocytosis
• Recovery
• Antibody synthesis bring resolution to symptoms,
  but the immunity is short lived because of little
  IgA in the respiratory tissues
• Diagnosis
• Four fold increase in specific serum IgG not
  routinely performed
• Prevention
• Prevent respiratory droplet transmission
• No vaccine

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Caliciviruses- Caliciviridae

• Classification
• Positive sense RNA
• Much like picornaviruses 27 nm
• Non-enveloped
• Human Disease
• Viral gastroenteritis
• Diarrhea, vomiting, variable fever, non-bloody
  stool
• Etiological agent is Norwalk Virus ( genus
  Norovius)
• Infects the intestinal brush border giving rise
  to a non-absorptive diarrhea

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Caliciviruses

• Viral Cycle
• Cycle is the same as picornavirus cycle
• Diagnosis
• Virus or viral antigen can be easily detected in
  the stool using RIA or Elisa
• Epidemiology
• P-P, indirect, fecal oral, mode of transmission
• Source are food, water, or shellfish
• 60 of all nonbacterial gastroenteritis involves
  Norwalk virus( esp in epidemics)
• 3 of gastroenteritis from day care facilities
• Prevention
• Interrupt fecal-oral transmission
• Chlorinate water, etc
• No vaccine

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Picornavirus- Aphthovirus

• Foot and Mouth Disease Virus
• Positive sense RNA, 24 nm,
• Non-enveloped, 7 serotypes
• Disease
• Foot and Mouth Disease
• Human
• Fever, salivation, vesiculation of mucous
  membranes
• Vesicles on palms, soles, fingers, toes
• Cattle
• Viremia leads to excretion of virus in urine
• Vesicles in mouth and on feet which rupture and
  release active virus
• Mortality is low
• But sick cattle do not thrive, protein synthesis
  decreases, they loose weight, and milk production
  decreases significantly

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Aphthovirus Foot and Mouth Disease

• Epidemiology Mode of Transmission
• Animal to person, direct contact
• Animal to person, ingestion of infected meat
• Animal to animal, urine contaminated materials
• Animal to animal, vesicular fluids for mouth and
  feet
• Concerns
• Virus survives for long periods outside of host
• Virus is resistant to inactivation
• Disease is highly contagious
• Control
• Destroy and burn (incinerate) infected animals
• Vaccines current vaccines provide only short
  term immunity
• New Vaccines using recombinant DNA technology
  are more promising, but are not perfected and not
  widely available

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Prions - Characteristics

• Classification
• Unconventional, non-microbial agents
• They are not viruses
• They are not bacteria
• Chemically, they are protease resistant,
  hydrophobic glycoproteins having no detectable
  nucleic acid component
• Filterable - lt 100 nm
• Modified host protein
• Resistant to inactivation by heat, chemicals, and
  radiation

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Prions - Diseases

• Diseases spongiform encephalopathies
• Human
• Creutzfeldt-Jakob Diseae
• Bovine Spongiform Encephalopathy mad cow
  disease
• Sheep
• Scrapie the original prion disease
• Cattle
• Bovine Spongiform Encephalopathy
• CJD progressive chronic dementia, ataxia, and
  myoclonus
• Death in 5 12 months

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Prion Diseases

• Pathogenesis hypothesis
• Normal human cells process a cell surface
  protein, cellular prion protein, PrPc
• Abnormal prion protein, scrapie prion protein,
  PrPsc, binds to the PrPc on human cells causing
  the cellular protein to change into the abnormal
  type which is shed from the cell and accumulates
  as amyloid-like plaques.
• Since the cell looses this protein, it replaces
  the PrPc, which is again changed by the PrPsc
  Cycle repeats itself
• Genetics PrPc is encoded by a single cellular
  gene. The changes in this gene are not completely
  understood, by appear to involve a single
  point-mutation

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Prion Epidemiology

• Scrapie was the original prion protein
• It developed in infected sheep
• Transmission correlated with the ingestion of
  sheep brains or material with contains sheep
  brains
• Cattle fed grain containing dried sheep brain
  protein develop bovine spongioform
  encephalopathy aka mad cow disease
• Humans who consume sheep brains or nervous system
  tissue from infected cattle develop CJD