• large, enveloped, dsDNA
• four structural elements
  • outer envelope
  • tegument
    • amorphus assemblage of virus encoded proteins that help initiate replication cycle
  • nucleocapsid- icosapentahedral array
  • inner core- proteins, viral genome

• different herpes virus are not distinguishable by electron microscopy
• most herpesviruses do not exhibit antigenic or DNA homology
  • exception: HSV-1 and HSV-2
  • both have long stretches of hamologous DNA

• derived from portions of nuclear and cytoplasmic membranes of the host cell that are pinched off by developing particles
• several viral glycoprotines inserted into the membranes

neurons

• monocyte and lymphocyte

• alpha
  • HSV-1, 2
  • VZV
  • herpes B virus
• beta
  • CMV, HHV6, HHV7
• gamma
  • EBV
  • HHV8

1. first contact is with gB with heparan sulfate R on host cell
2. second contact is with gC with heparain sulfate R and C3b
3. gD will bind and trigger fusion binding to HveA/HveC
4. gL allow membrane transport and maturation of gH

• immediate early proteins- DNA binding proteins important in regulating gene transcription
• early proteins- TF's, thymidine kinase; DNA polymerase
• late proteins- structural proteins, assembly

1. local replication in epithelial cells
2. cell lysis and inflammatory response
3. multinucleated giant cells (intranuclear inclusions)
4. virus travel along sensory nerves to sensory nerve root ganglia where it can become latent

1. nucleocapsid docks with nuclear membrane and delivers genome into nucleus
2. transcription by cellular DNA dependent RNA polymerase
   • viral proteins block cellular DNA and mRNA synthesis
   • different groups of protein made (SEE OTHER FLASHCARD)
3. DNA combines with capsid proteins to form nucleocapsid which buds from the nuclear membrane
4. viral particle is processed in golgi to endocytic vesicle
5. virus buds by fusion with host cell membrane and is either released as a free virus or may spread from cell to cell
6. viral glycoprotiens on host cell trigger cell fusion leading to giant cells
7. during latnecy, viral DNA remain dormant as episomal DNA or replicate

• retrograde axonal transport
• mediated by dynein mediated, minus end microtubular transport

• UV light
• stress
• trauma
• immunosuppression

Travel via anterograde axonal transport via kinesin heavy chain mediated positive end microtubular transport.

• local and systemic immunity
• acquired immune response
  • neutralizing Ab
  • cell mediated immunity
    • CD4 (Th1)
    • CD8 T cells
• innate immunity
  • NK cells
  • plasmacytoid dendritic cells (pDC) (IFN gamma)
  • toll like R's
    • TL3, 4, 7/8, 9

• first episode HSV
• no concurrent HSV Ab's

• first episode HSV
• evidence of prior exposure to alternative type
  • HSV-1 with Ab to HSV-2
  • HSV-2 with Ab to HSV-1

• lesions that do not develop to full vesicular stage
• sometimes seen with pre-emptive therapy

• reactivate HSV that is the same type as existing serum Ab

• incubation period: 2-12 days
• course: 10-14 days
• gingivostomatitis
  • generally in children less than 5 years old
  • vesicles with rapid ulceration involving soft palate, buccal mucosa, tongue, and floor of mouth
  • oral pain
  • cervical lymphadenopathy

• incubation period: 2-7 days
• fever, anorexia, malaise, tender regional lymphadenopathy
• vesicular rash more severe in primary infection
• may have aseptic meningitis (clue: headache)
  • inflammation of sacral nerve roots may lead to urinary retention (more common in women)
• lesions may take several weeks to heal
• lesions may be severe in immunocompromised hosts

• most recurrences happen within first two years of primary genital infection
• mostly of HSV-2
• prodromal symptoms
  • pain
  • burning
  • tingling
  • itching
• sterotyped lesion at each recurrence (usually at the same spot)
• lesions fewer in number, less severe, less systemic symptoms, more rapid healing (8-10 days)

• most common in HSV-2
• risk increased with recent acquisition and higher frequency of symptomatic recurrences
• half of shedding within 7 days of symptomatic occurence
  • but there is great variability within shedding

• seen in HSV-1 (but with neonates: HSV-2)
• some only have keratitis alone
• frequent lid involvement
• dendritic appearance
• VZV may involve cornea in a similar fashion
• eye involvement due to either HSV or VZV may be recurrent

• involvement of nailbed, may resemble bacterial paronychiae
• medical personel: HSV-1
• general population: HSV-2
• fever, pain, axillary adenopathy
• vesicular lesion at nail margin
• heal in 2-3 weeks, may be recurrent

• chronic skin lesions
• esophagitis
• pneumonia (RARE)
• dissemination (RARE)

• picked up as baby moves through birth canal
• may lead to:
  • seizures
  • blindness
  • psychomotor retardation
  • spasticity
  • developmental delay
  • death
• may be HSV-2 or 1
• risk of infection- up to 30% if mother has active lesions at birth
  • caesarian indicated

• clinical based on characteristic lesions
• Tzanck prep: multinucleated giant cells
• viral culture (takes longer)
  • sensitivity lower for recurrent lesions
  • declines rapidly as lesions begin to heal
• PCR (rapid)
  • 3-5x more likely to be positive than culture

• acyclovir and derivatives (DOES NOT CURE THE VIRUS)
  • shortens duration fo symptoms and viral shedding
  • well tolerated
  • may also suppress recurrences
  • emergence of acyclovir R in patients with HIV infection or long term prophylaxis
• vaccines in development

• alpha herpesvirus
• similar genetic organization to HSV
• cell to cell spread within 8-10 hrs of infection
• multinucleated giant cells
• neuronal latency: reactivation leads to herpes zoster or "shingles"

• childhood illnes (half before school entry)
• usually in late winter/early spring
• more so in temperate climates
  • 90% of US adults have prior exposure to chicken pox
  • half of Puerto Rican miliatry recruits have seropositive results
• transmission
  • highly contagious
  • person to person via respiratory route
  • may be transmitted 3-5 days before rash
• highest mortality with VZV seen in adults

• incubation period: 14-15 days
• symptoms
  • fever
  • rash begins on scalp or trunk, spreading to extremities
• superficial vesicles in different stages of development (vesicles, pustules, scabs)
• vesicles may occur on mucous membrane but quickly become ulcers

• clinical diagnosis based on characteristic lesions
• Tzanck prep: multinucleated giant cells
• tissue culture, variety of cell lines
• direct immunofluorescence

• hepatitis, pneumonitis, encephalitis
• superinfection of cutaneous lesions, especially with S. aureus, group A beta streptococcus
• Reye's syndrome: encephalopathy, liver disease
  • associated with aspirin consumption
  • 30% follow varicella
• Guillain Barre syndrome: ascending motor paralysis

Note that skin lesions will not cross the MIDLINE of the body.

• lifetime risk at least 20%
• incidence increase with advancing age or immunosuppression
  • half of all people living until age 85 will develop zoster

• latency in dorsal root ganglia (similar to HSV)
• recrudescence in a dermatomal distribution
• prodromal pain (severe, can be persistent and if it is, it is called post-herpetic neuralgia)
• unilateral, involving 1-3 dermatomes (50% thoracic)

• can have associated meningitis
• can disseminate to:
  • liver (hepatitis)
  • lung (pneumonitis)
  • brain (encephalitis)
• post herpetic neuralgia
  • persistent pain for more than a month
  • incidence increases with advancing age
  • may be able to prevent with antiviral therapy (experimental)

• the live attenuated vaccine
  • has shown to protective efficacy with household exposure