Persistence and Transition of
Epstein-Barr Virus Genotypes in
the Pathogenesis of Oral Hairy
Leukoplakia
Benjamin L. Thompson
Epstein-Barr Virus (EBV)
• EBV is a herpes virus capable of causing
tumors.
• EBV is associated with numerous diseases.
• The human EBV virus establishes latent, life-
long infection in more than ninety-five percent of
the human adult population.
• Inactive memory B lymphocytes in peripheral
blood are believed to be a reservoir of
persistence of latent EBV.
Epstein-Barr Virus (EBV)
• EBV can effectively replicate in normal
oral epithelial cells.
• Research suggests that EBV may be
detected in oral tissues as a latent
infection.
• As in all herpes viruses, EBV has latent
and lytic (productive) phases in its life
cycle
Oral Hairy Leukoplakia (OHL)
• OHL is a possible lesion during HIV infection
that is characterized by productive EBV
replication in oral epithelial cells.
• The occurrence of OHL increases as the CD4 T
cell counts fall and is thought to indicate a rapid
progression to AIDS.
• Treatment of patients with OHL, with drugs that
inhibit EBV replication, resolves the lesion.
• However, treatment does not eliminate latent,
lasting EBV infection, and oral replication of EBV
and OHL commonly reappears following
treatment.
Oral Hairy Leukoplakia (OHL)
• OHL is chronically characterized by
coinfection with multiple EBV strains.
• EBV in OHL evolves into new substrains,
through nucleotide mutations, and into
new variants, through intrastrain and
interstrain recombination
Rationale
• To determine whether oral epithelial
tissues harbor persistent EBV infection.
• To identify the origin of the EBV replicating
in OHL.
• To investigate EBV interactions between
the oral epithelial and blood reservoirs of
infection.
Sequence patterns in EBV
Data tables
• In 3 subjects, EBV replication recurred in the
tongue after treatment with valacyclovir.
• In 6 subjects, EBV replication did not recur in
the tongue after treatment with valacyclovir.
• Three additional subjects never manifested HLP
or EBV replication in the tongue but were treated
with valacyclovir as control subjects
EBV response-reactivation group.
EBV replication negative control
group.
Results
• Treatment with valacyclovir did not
consistently alter the composition of the
EBV genotype populations in the blood.
• Studies have shown that EBV in peripheral
blood mononuclear cells (PBMC) is
predominantly latent
• Only a small percentage of EBV-infected
cells support EBV replication.
Results
• EBV replication is not required to sustain
EBV infection of the tongue.
• Tongue infection with multiple EBV
genotypes is not limited to OHL.
• Normal tongue epithelial tissues may
harbor multiple nonreplicative EBV
infections that could serve as a local
reservoir of EBV reactivation.
Results
• Systemic treatment with valacyclovir
suppressed EBV replication in the tongue
and in the blood.
• EBV replication may not be required for
the entry of new EBV genotypes into
tongue epithelial tissue.
Results
• PBMCs and tongue epithelial tissue
exchange EBV genotypes and that some
new EBV genotypes may enter the tongue
as an exogenous infection.
Results
• Some EBV genotypes may evolve into new
substrains through nucleotide mutation
• In subject 8, several substrains of the EBV
genotype 3c sequence pattern evolved during
the study period
• Tongue and blood specimens obtained after
treatment with valacyclovir contained an
identical and unique substrain 4 that was not
present in previous tongue or blood specimens.
Substrain sequence variation
Conclusions
• EBV genotypes were detected in every
tongue specimen examined.
• Some EBV genotypes were found to
persist in tongue tissue for 56-70 days.
• EBV genotypes persisted in the tongue
even without replicating.
Conclusions
• EBV genotypes may transition from
PBMCs to the tongue
• Nonreplicative EBV genotypes persisting
in the tongue can reactivate and replicate
in the tongue.
• Other EBV genotypes may enter the
tongue as exogenous infection
Conclusions
• The data provided evidence for EBV
genotype exchange between the blood
and the tongue, especially for blood
serving as a source of EBV for the tongue.
• The data also demonstrated tissue-
specific segregation of EBV genotypes.
Conclusions
• The transition of EBV genotypes from
PBMCs to tongue epithelial tissues, during
treatment with valacyclovir, suggests that
EBV may enter oral epithelial tissue as a
cell-associated latent infection
References
• Walling, D.M. et al. 2004. Persistence and
transition of Epstein-Barr virus genotypes in the
pathogenesis of oral hairy leukoplakia. Journal
of Infectious Diseases. 190: 387-395.
• University of Michigan Medical School. Medical
gross anatomy
http://www.med.umich.edu/lrc/coursepages/M1/a
natomy/html/surface/head_neck/oral_cavity.jpeg
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