Download microbiology ch 41[9-4

Micro Ch 41
Alpha Herpes Viruses: Herpes Simplex Viruses and Varicella-Zoster Virus
Key Concepts
 Pathogen: Alpha herpes viruses: ds DNA viruses that include HSV types 1 & 2 and varicella-zoster virus (VZV)
 Encounter: high incidence of infection in humans; almost all people get HSV type 1; most asymptomatic
 Entry: HSV by direct contact; VSV from infectious aerosols
 Replication and Spread: establish latent infections following primary infection; latency makes it last for life and
can lead to reactivation of virus replication and recurrent outbreaks
 Damage: HSV’s cause oral and genital herpes (occasionally encephalitis); VZV causes chickenpox and shingles
 Treatment: alpha herpes viruses treated w/antiviral agents (acyclovir); antiviral therapy doesn’t prevent future
 Prevention: VZV vaccines available for chickenpox and shingles
Encounter
 HSV-1 spread by exchanging saliva; nearly 2/3 of adults have antibodies to HSV-1
 HSV-2 acquired by oral-oral and oral-genital contact; primarily spread by genital-genital contact
o 1/5 of all adults infected w/HSV-2, depending on nature and number of sexual encounters
 HSV-1 or HSV-2 cause severe disease in neonates if exposed during birth to mother w/primary infection
 VZV usually acquired through respiratory route; contact w/vesicular fluid or secretions can occur; primary
disease much more contagious than HSV-1 and HSV-2 because direct contact not required
o Breakthrough disease – mild form of chickenpox occurring in vaccinated pts; can transmit virus
 Most infections w/HSV-1 or HSV-2 asymptomatic; can still transmit virus by shedding from epithelial surfaces
even if lesions not large enough to be noticeable
Entry
 Membrane envelop causes them to be fragile and susceptible to drying and inactivation by heat, mild detergent,
and solvents; infection usually requires direct contact
 Thick keratin layer of superficial epidermis prevents HSV from getting to receptors; mucous membranes not so
strong barrier, so they get in here
Spread and Replication
 Infection begins w/attachment of virus particles to susceptible cells; bind to cells through interaction of
glycoproteins w/heparan sulfate chains on cell-surface; binding brings virus into close proximity to other cellsurface molecules that function as entry receptors
o HSV-1 & HSV-2 preferentially use different receptors to infect different cell types at various portals of
entry and in brain
o Binding of viral glycoprotein to entry receptor triggers fusion of virion envelope and PM (or membrane
of endosome); causes release of viral nucleocapsid into cytoplasm
o Transport of nucleocapsid to nuclear pores; viral genome released into nucleus
o In cell capable of supporting virus replication, virus genes transcribed in temporal fashion
o If cell latently infected, viral genome circularizes in nucleus and persists as episome w/minimal
transcription of viral genes
o Virus gains access to nerve cell endings that extend toward epidermis and is transported to nerve cell
bodies in peripheral sensory and autonomic ganglia, where latent infections established
 Productive infection: infection where virus replication occurs; immediate-early genes transcribed w/assistance
of transcription factors carried in virion tegument (space between nucleocapsid surface and envelope)
o Proteins encoded by immediate-early genes activate expression of early genes (protein products
required to replicate viral DNA)
o Late genes expressed after DNA synthesis; encode proteins that assemble and comprise progeny virions
 Glycoproteins insert into cell membranes
 As new viral nucleocapsids assembled in nucleus, they bud through inner nuclear membrane to
acquire temporary envelope, which they lose by fusing w/outer nuclear membrane
 Final viral envelope w/full set of viral glycoproteins acquired by budding into cytoplasmic
vacuoles derived from Golgi apparatus; vacuoles transport mature virions to surface for release
by exocytosis

As herpes viruses released from host cell, they immediately attach to and penetrate adjacent cells; diseases
characterized by local spread and progression of lesions; HSV rarely spreads systemically
o VZV causes systemic disease because of capacity to infect and be transported by circulating WBCs that
deliver virus to multiple organs and skin by cell-to-cell contact
Host Defenses
 Can prevent Sx in HSV-1 and HSV-2, but can’t prevent latent infections and can’t eliminate latent virus (latently
infected cells don’t trigger sterilizing immune responses)
 Antibodies and T cells responsive to viral antigens
o Anti-herpes virus antibodies play minor role in recovery from primary HSV or VZV because they develop
too late to modify course of infection; no impact on recurrent disease either
o Antibodies contribute to prevention of primary disease
 Cell-mediated immune mechanisms most important for recovery from HSV or VZV
o Relevant immune effector cells gradually mature during first month of infant’s life; until maturation
complete, herpes infections would be devastating; by 1 month of age, infection well-tolerated
o Reactivation of VZV leading to zoster occurs w/increasing frequency as function of age (senescence of
antiviral immune responses)
Damage
 HSV and VZV destroy epithelial cells in which they replicate in skin and mucous membranes, causing vesicular
lesions that rupture, leaving shallow gray-white ulcers on erythematous base
o As virus replication and spread contained by immune responses (primarily innate and cell-mediated
responses), epithelium fully regenerates
 Primary and recurrent HSV lesions usually localized (spread of virus restricted to regional nerves)
o During primary disease, sequential lesions resulting from reseeding of adjacent epithelial sites by
neurons infected during earlier waves of epithelial replication
o Damage or inflammation of nerves causes itching, tingling, burning, or pain; similar sensations are
prodrome that recurrent lesions about to develop
o Reactivation of latent HSV by sunburn, systemic infections, immune impairment, emotional stress, and
menstruation
o Reactivated HSV travels down axonal processes to infect contiguous mucocutaneous epithelial cells
 Site of HSV inoculation governs manifestations of primary and recurrent disease
o Corneal infections: immune responses that damage cornea; may cause blindness needing corneal
transplant for recovery of vision
o Primary genital herpes (HSV-2) can progress to meningitis or affect autonomic functions governing
urination and defecation
o HSV-1 can pass from peripheral nerves to CNS to cause encephalitis (destructive inflammation of
unilateral focal nature)
 Accounts fo 95% of all cases of sporadic disease in children and adults in developed countries
o Immunocompromised at risk for infections of skin, lungs, esophagus, liver, and brain
 VZV chickenpox: systemic febrile disease w/mucocutaneous lesions; cells of lymphatic system infected in
respiratory tract; spread of virus-infected WBCs throughout lymphatic system induces types of cytokine
responses that result in fever, malaise, and headache
o Secondary viremia – circulating WBCs transmit virus to epithelial cells of skin and mucosa; characteristic
lesions of chickenpox occur
o Latent infections established in peripheral ganglia
o Complications: cerebellar ataxia in otherwise healthy children and encephalitis in immunocompromised
 Zoster lesions (shingles) – appear clustered on body surface along dermatome
o Neurological Sx (primarily pain) much more severe than for HSV recurrences (more viral damage to
affected nerves and supporting cells)
o Can cause severe disseminated disease in immunocompromised
Diagnosis
 Presentation w/history usually sufficient
 Scrapings from lesions processed for PCR w/probes for viral DNA or stained directly w/specific fluoresceinlabeled antibodies that bind viral antigens

Definitive diagnostic is virus isolation from cell culture; HSV grows well in wide variety of fibroblast and epithelial
cell lines from animals or humans
o Replicating viruses induce changes in cell shape and appearance
o VZV more difficult to propagate in culture; more fastidious about cell type
Treatment
 Acyclovir – analog for guanosine; phosphorylated by herpes virus enzymes but not cell enzymes; incorporated
into viral DNA as chain-terminating nucleotide; active principally in herpes-infected cells
 Pencipclovir – guanosine analog used topically; poor oral bioavailability
 Valacyclovir – prodrug of acyclovir; improved oral bioavailability; treatment of either HSV or VZV
 Famciclovir – prodrug of penciclovir; improved oral bioavailability; treatment of either HSV or VZV
 Drugs may be administered IV or PO, depending on condition being treated
 Prevent worst of disease, but don’t effect cure because they don’t prevent entry of virus into neurons and can’t
eliminate latent viral genomes
Prevention
 Appropriate to avoid sexual contact during active genital herpes infections; reduces, not prevents, transmission
 Pts w/chickenpox should be isolated and vaccination offered to family members or other contacts
o Exposed immunodeficient children not candidates for vaccination; protected by administration of
specific human Ig promptly after exposure
o Live, attenuated VZV vaccine prevents chickenpox in normal and some immunocompromised children
 Vaccine virus establishes latent infection; reactivation may lead to mild cases of shingles
o New formulation boosts anti-VZV cellular immunity in older people and protects from shingles
o Isolate patients w/primary VZV because virus can be transmitted via aerosols
 People w/active herpetic lesions shouldn’t be allowed contact w/newborn infants