Herpes, Varicella, and Small Pox

Question 1

Herpesviridae

Answer 1

• Large group of viruses widespread throughout the animal kingdom
• Human herpesviruses are ubiquitous
• Many individuals become infected at an early age
• Latent infection and recurrent disease are trademarks of herpesvirus infection
• Linked to human cancer
  
  • EBV ⇒ Burkitt’s lymphoma and nasopharyngeal carcinoma

Question 2

Herpes Simplex Virus (HSV)

Overview

Answer 2

• First human herpesviruses recognized
• Two types of HSV ⇒ types 1 and 2
  
  • Share many common Ag
  • Have specific glycoproteins that distinguish them
  • Differ in many biological characteristics

Question 3

HSV

Structure

Answer 3

• Icosahedral capsid
• Capsid enclosed in a glycoprotein-containing envelope
  
  • Acquired as it buds through host cell nuclear membrane
• Tegument ⇒ space between envelope and capsid
  
  • Contains viral proteins
• Sensitive to acid, solvents, detergents, and drying

Question 4

Herpesvirus

Genome

Answer 4

Genomes of the five well-defined HHV have a unique organization:

• Long, double-stranded linear DNA molecules
• Several repeated and inverted sequences

Question 5

HSV

Glycoproteins

Answer 5

HSV virions contain at least 11 glycoproteins:

• gB, gD, and gH ⇒ attachment and entry into the cell
• gD ⇒ essential for infection
  
  • Varies little in structure and antigenicity between HSV-1 and HSV-2
• gC differs extensively between HSV-1 and HSV-2
  
  • Antisera to gC generally type specific

Question 6

HSV

Infection

Answer 6

• Can infect most types of human cells & other animals
• Virus receptor expression on many types of cells ⇒ broad host range
• HSV-1 and HSV-2 can infect the same tissues and cause similar diseases
• Predilection for specific infection sites and disease patterns
• Infection generally results in:
  
  • Lytic or productive infections of fibroblast and epithelial cells
  • Latent infections of neurons

Question 7

HSV

Cell Entry

Answer 7

• HSV-1 initially binds to heparan sulfate
  
  • Proteoglycan found on the outside of many cell types
• Then interacts w/ a protein closer to the cell surface
• Major route of HSV penetration is fusion at the cell surface membrane
• Virions can also enter cells by endocytosis
• Nucleocapsid enters cytoplasm
• Capsid docks w/ nuclear membrane
• Delivers the genome into the nucleus ⇒ where transcription and replication occur
• Virion proteins carried in the tegument also delivered into the cell

Question 8

HSV

Protein Synthesis

Answer 8

Transcription and protein synthesis occurs in 3 regulated phases:

• Immediate-early (IE)
  
  • DNA-binding proteins
  • Stimulate DNA synthesis and promoter transcription of early viral genes
• Early (E)
  
  • Mostly of enzymes required for replicating the viral genome
    
    • DNA-dependent DNA polymerase
    • Scavenging proteins
    • Deoxyribonuclease
    • Thymidine kinase
    • Ribonucleotide reductase
  • Provide substrates for replication, even in cells not undergoing DNA synthesis (neurons)
• Late (L)
  
  • Many copies of these proteins are required for virion assembly
  • Each phase is required for progression to the next

Question 9

HSV

Dissemination

Answer 9

• Capsid proteins are transported to the nucleus
• Assembled into empty procapsids
• Filled w/ DNA
• DNA-containing capsids associate and bud from viral glycoprotein-modified portions of the nuclear membrane
• Virus also released when cell lysis occurs

Question 10

HSV

Primary Infection

Answer 10

• HSV usually causes a localized infection
• Enters body via mucosal membranes or breaks in the skin
• Viral replication @ site of entry ⇒ inapparent or produce vesicular lesions
  
  • Replicates in cells @ base of lesion
  • Vesicular fluid contains infectious virus
• Lesion generally heals w/o producing a scar

Question 11

HSV

Cellular Effects

Answer 11

• HSV can cause lytic infections of a variety of cell types
• HSV replication generally leads to cytolysis due to:
  
  • Virus-induced inhibition of cellular macromolecular synthesis
  • Degradation of host cell DNA
  • Membrane permeation
  • Cytoskeletal disruption
  • Senescence of the cell

Question 12

HSV

Latency

Answer 12

• Virus spreads to adjacent cells and innervating neurons
• After infection of the neuron, nucleocapsid transported to cell nucleus ⇒ virus latency
• Latent infection of neurons results in no detectable cytopathic alteration of neurons
• Few, if any virus-specific proteins detectable during latent phase

Question 13

HSV

Reactivation

Answer 13

• Virus can be activated from the neuron by various stimuli (e.g., stress, trauma, fever, or sunlight)
  
  • Reactivation occurs despite presence of neutralizing Ab
• Trigger usually involves stress w/ ± transient depression of CMI
• Virus travels back down the nerve ⇒ lesions at the dermatome
• Recurrent infections usu. less severe, more localized, and of shorter duration

Question 14

HSV

Host Immune Response

Answer 14

• During primary infection, interferon and NK cells help limit progression of infection
  
  • IFN ⇒ ⊕ NK cells ⇒ recognize HSV-infected targets and lyse cells
• MΦ phagocytize viral Ag ⇒ present to CD4 helper T cells and B cells ⇒ ⊕ antigen-specific immunity
• Control and resolution requires both humoral and cellular immunity:
  
  • Ab vs virus glycoproteins ⇒ neutralize extracellular virus ⇒ limits spread
  • Ab vs HSV-1 protective against future challenges by other strains of HSV-1
    
    • Also to some extent against infections w/ HSV-2 and vice versa
• Virus can escape neutralization and clearance by:
  
  • Direct cell-to-cell spread
  • Latent infection of the neuron
• CMI essential for controlling and resolving HSV infections
  
  • Absence of CMI ⇒ dissemination to vital organs and brain
• Cellular immune and inflammatory responses ⇒ immunopathologic ∆ ⇒ sx exacerbation

Question 15

HSV

Transmission

Answer 15

• Virus found in oropharyngeal secretions
  
  • Spreads by direct contact
  • Presumably requires salivary exchange
• HSV-2 primarily transmitted by sexual intercourse
  
  • May infect the genitalia, anorectal tissues, or oropharynx
  • Associated w/ symptomatic or asymptomatic primary infection or recurrences
  • Asymptomatic recurrences are especially likely in females
  • May shed the virus in cervical secretions w/o any clinical illness
  • Most new cases of genital HSV result from sexual contact w/ individuals who have active lesions
  • Should refrain from sexual intercourse when prodromal sx or lesions occur
  • Can resume only after lesions are completely re-epithelialized
  • Virus can be isolated from lesions even when crusted
• Vertical transmission may also result from:
  
  • Maternal viremia during primary HSV-2 infection
  • Ascending in utero infection
  • Infection during delivery

Question 16

HSV

Diagnosis

Answer 16

• Rapid test available
• Culture genital lesions or CSF for HSV
• Microscopic examination of cells at the base of lesion ⇒ Tzanck smear
  
  • Multinucleated giant cells
  • Cowdry’s type A inclusion bodies
• Enzyme immunoassay, IF assays, and in situ DNA probe analysis are available

Question 17

HSV

Treatment and Prevention

Answer 17

Tx w/ oral or IV antivirals

No effective vaccine available

Question 18

Varicella-zoster virus (VZV)

Overview

Answer 18

• VZV causes chickenpox (varicella)
• Recurrence causes herpes zoster (Shingles)
• VZV shares many characteristics w/ HSV including:
  
  • Infects PNS (the ganglia)
  • Characteristic blister-like lesions
  • Spread via respiratory route

Question 19

Varicella-zoster virus (VZV)

Structure

Answer 19

• Production of thymidine kinase and other viral specific enzymes
• VZV particle morphology is typical for a herpesvirus
• Genome of VZV is smaller than HSV

Question 20

Varicella-zoster virus (VZV)

Pathogenesis

Answer 20

Predominant means of spreading VZV is by the respiratory route.

Question 21

Varicella

Answer 21

“Chickenpox”

Primary infection caused by VZV

• Usually a disease of childhood
• Usually symptomatic, although asymptomatic infection may occur
• Incubation period of about 14 days
• Characterized by fever and maculopapular rash
  
  • Lesion progression: maculopapular → vesicle on M/P base (“dew drop on a rose petal”) → pustule → crust → scab
  • Successive crops of lesions appear for 3 to 5 days
• At any given time, all stages of skin lesions can be observed
• Rash is generalized
  
  • More severe on trunk than extremities
• Notably present on the scalp
  
  • Distinguishes it from many other diseases
• Lesions are very pruritic ⇒ scratching ⇒ ± bacterial superinfection and scarring
• Varicella is a risk factor for acquiring invasive infection w/ Group A Strep (S. pyogenes)
• Mucous membrane lesions in the mouth, conjunctivae, and vagina typical
• ± Thrombocytopenia ⇒ ± hemorrhagic rash
• Primary infection of adults usu. more severe than for children
• ± Interstitial pneumonia (20-30% of adult pts) and may be fatal
• Extremely severe, disseminated infection occurs in immunocompromised pts

Question 22

Herpes Zoster

Answer 22

Recurrent infection with VZV

• Occurs sporadically in pts who had varicella infection in the past
• Appearance of chickenpox-like lesions usually preceded by severe pain in innervated area
• Rash usually unilateral and occurs in one or more adjacent dermatomes
  
  • Small, closely spaced maculopapular lesions on erythematous base
  • Lesions vesiculate rapidly and often coalesce
• Following a zoster infection, pts may experience a chronic pain syndrome ⇒ postherpetic neuralgia
  
  • Can persist for months to years
  • Occurs in up to 30% of pts who develop zoster after 65

Question 23

VZV

Diagnosis and Treatment

Answer 23

• Dx techniques for VZV similar to HSV except virus culture much more difficult for VZV
• No tx for varicella indicated in normal immunocompetent children
• Varicella in adults may be treated w/ acyclovir

Question 24

VZV

Prevention, and Control

Answer 24

• VZV spreads via respiratory route
• Isolation of infected individuals and avoidance of contact may ↓ transmission
• Live attenuated vaccine for VZV induces protective Ab
  
  • Effective as a prophylactic tx even after exposure to VZV
  • Promotes protection in immunodeficient children
  • Recently been approved for use in normal immunocompetent children

Question 25

Poxviruses

Major Features

Answer 25

• Largest, most complex viruses
• Complex, oval to brick-shaped morphology w/ internal structure
• Multiple viruses in both categories 1° infect non-human vertebrates
• Two viruses only infect man ⇒ variola virus (Smallpox) and molluscum contagiosum
• DNA viruses that replicate in the cytoplasm
• Assembly in cytoplasmic inclusion bodies ⇒ B-type inclusions, previously known as Guarnieri’s bodies
  
  • Where it acquires its outer membranes

Question 26

Human

Poxviruses

Answer 26

Orthopoxvirus: Variola virus (Smallpox)

Molluscipoxvirus: Molluscum contagiosum

Question 27

Poxviruses

Genome and Proteins

Answer 27

• Linear, double-stranded DNA genome w/ fused ends
• Codes for wide range of proteins
• Encodes and carry all proteins necessary for mRNA synthesis
• Encodes proteins for DNA synthesis, nucleotide scavenging, and immune escape mechanisms
• Carry more proteins in particle
• Produce multiple proteins that interfere w/ host defenses

Question 28

Smallpox

Pathogenesis

Answer 28

Human is only host

Causes a disseminated respiratory tract infection

• Incubation: 5-17 days
• Initial replication in upper respiratory tract
• Systemic dissemination by lymphatics and cell-associated viremia
• Primary viremia ⇒ replication in multiple organs
• Secondary viremia often occurs
  
  • Fever 3 days before rash
• Slow-onset centrifugal rash due to hemorrhage of small blood vessels
  
  • Extensive pustules all at the same stage, usu. involves palm and soles
• Mortality:
  
  • 15–40% (Variola major)
  • 1% (Variola minor)

Question 29

Smallpox

Immunity and Control

Answer 29

• Virus encodes immune escape mechanisms
• Immunization w/ related vaccinia virus
• Disease declared “eradicated” in 1980
• CMI and humoral immunity important for resolution
• Ab: primary mode of control after immunization
• Cell mediated immunity: primary control during infection due to cell-to-cell spread

Question 30

Smallpox

Eradication

Answer 30

Properties of small pox that led to its eradication:

• Viral Characteristics
  
  • Exclusive human host range
  • No animal reservoirs or vectors
  • Single serotype
  • Immunization protected against all infections
  • Animal and human poxviruses share antigenic determinants
  • “Safe” live vaccines prepared from animal poxviruses
• Disease Characteristics
  
  • Consistent disease presentation w/ visible pustules
    
    • ID of sources of contagion allowed quarantine and vaccination of contacts
  • Distribution of smallpox rash
    
    • Most dense on the face, arms and hands, legs and feet
    • Trunk has fewer pocks than the extremities
• Vaccine
  
  • Stable, inexpensive, easy-to-administer vaccine
  • Presence of scar indicating successful vaccination
• Public Health Service
  
  • Successful worldwide WHO program combining vaccination and quarantine

Question 31

Molluscum contagioisum

Answer 31

• Spread by contact w/ lesion
• Results in wart-like growth w/ caseous plug
  
  • Warts usually occur in clusters
• Incubation: 2-8 weeks
• Characteristics: Eosinophilic cytoplasmic inclusion in cells
• Self-limiting: disappears in 2-12 months
• Treatment: iodine, liquid nitrogen

Question 32

Poxviruses

Disease Mechanisms

Answer 32

• Smallpox initiated by respiratory tract infection and spread mainly by lymphatic system and cell-associated viremia
• Molluscum contagiosum and zoonoses are transmitted by contact
• Virus may cause initial stimulation of cell growth and then cell lysis
• Virus encodes immune escape mechanisms
• Cell-mediated immunity and humoral immunity are important for resolution

Question 33

Smallpox Vaccination

Complications

Answer 33

• Complications vary w/ vaccine virus, age of vaccine and underlying medical problems
• Encephalitis, eczema vaccinatum, progressive vaccinia, (myocardial infarction)

Question 34

Varicella vs Small Pox

Answer 34