Pathogenesis The Epstein-Barr virus (EBV), a ubiquitous herpesvirus estimated to infect 90% of the world's population, has been

linked to a growing number of diseases, especially in immunocompromised hosts. Like all herpesviruses, EBV establishes a life-long, persistent infection of its host. Hairy leukoplakia is associated with productive EBV replication. Inhibition of EBV replication with antiviral therapy results in resolution of the hairy leukoplakia lesion within 1-2 weeks. However, productive EBV replication may also occur in normal tongue epithelial cells, without generating the characteristic histopathology of hairy leukoplakia. Thus, productive EBV replication appears to be necessary but not sufficient for the pathogenesis of hairy leukoplakia. The cofactors that contribute to the pathogenesis of the lesion have not yet been identified. Hairy leukoplakia and the biology of EBV infection in this disease have some unique features that likely contribute to the pathogenesis of this lesion. 1. Hairy leukoplakia frequently contains multiple, co-infecting, EBV strains. In hairy leukoplakia, the productively replicating EBV undergoes genetic recombination and sequence mutation, generating a complex population of multiple EBV strains, substrains, and recombinant variants. The pathogenicity of EBV may be enhanced by this genetic heterogeneity. 2. Many EBV genes that typically are associated with latent EBV infection are surprisingly expressed during productive EBV replication in hairy leukoplakia. Some of these genes are known to have profound effects on cellular proliferation, differentiation, and apoptosis, and these EBV gene products may induce the cellular changes that ultimately give rise to the histopathologic features of hairy leukoplakia. Interestingly, many of the "latent" genes expressed in hairy leukoplakia also sustain high rates of genetic mutation in hairy leukoplakia, potentially altering their pathogenicity or their immunogenicity.

3. There is a marked decrease or an absence of Langerhan's cells in hairy leukoplakia biopsy tissues. Langerhan's cells are the antigen-presenting immune cells that are required for an immune system response to the viral infection. This deficiency of Langerhan's cells may permit EBV to persistently replicate and escape immune recognition. The pathogenesis of hairy leukoplakia is clearly complex, potentially requiring a convergence of factors including EBV co-infection, productive EBV replication, EBV genetic evolution, expression of specific EBV "latent" genes, and immune escape. All of these factors are likely facilitated by local and systemic host immunodeficiency. The study of hairy leukoplakia will elucidate mechanisms of EBV molecular pathogenesis and immunopathogenesis that may be applicable to other EBV-associated diseases.

Prognosis and complication No cases of malignant transformation in patients with preexisting OHL have been reported, although mild cellular atypia has been described. Patients might complain for its unsightly appearance, in which cases, therapeutic intervention might be indicated. OHL can be an early, if not, the first sign of HIV infection. OHL can be used as a convenient clinical marker of HIV-disease severity, since most affected patients have CD4(+) T-cells counts < 400/mm3. In addition, OHL has a reliable prognostic value in the natural history of HIV disease. The estimated rate of progression to AIDS at one year for subjects with OHL varies from 10% to 48% and at two years from 24% to 63%. Patients with OHL are also more likely to develop lymphomas.

Further reading 1. Triantos D, Porter SR, Scully CM, Teo CG. Oral hairy leukoplakia: clinicopathological features, pathogenesis, diagnosis, and clinical significance. Clin Infec Dis 1997; 25:1392-6. 2. Webster-Cyriaque J, Middeldorp J, Raab-Traub N. Hairy leukoplakia: an unusual combination of transforming and permissive Epstein-Barr virus infections. J Virol 2000; 74:7610-8. 3. Palefsky JM, Berline J, Greenspan D, Greenspan JS. Evidence for trafficking of Epstein-Barr virus strains between hairy leukoplakia and peripheral blood lymphocytes. J Gen Virol2002; 83:317-21.

4. Walling DM, Clark NM, Markovitz DM, Frank TS, Braun DK, Eisenberg E, Krutchkoff DJ, Felix DH, Raab-Traub N. Epstein-Barr virus coinfection and recombination in non-human immunodeficiency virus-associated oral hairy leukoplakia. J Infect Dis. 1995;171:1122-1130. 5. Resnick L, Herbst JS, Ablashi DV, et al. Regression of oral hairy leukoplakia after orally administered acyclovir therapy. JAMA. 1988;259:384-388. 6. Walling DM, Flaitz CM, Nichols CM, Hudnall SD. Non-lytic productive EBV replication in normal tongue epithelial cells in vivo. Abstract presented at the Ninth Biennial Meeting of the International Association for Research on Epstein-Barr Virus and Associated Diseases, 2000; New Haven, Connecticut.