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. 2004 Apr;78(7):3455-61.
doi: 10.1128/jvi.78.7.3455-3461.2004.

Molecular evidence for rhesus lymphocryptovirus infection of epithelial cells in immunosuppressed rhesus macaques

Jeffery L Kutok  1 , Sherry Klumpp, Meredith Simon, John J MacKey, Vuong Nguyen, Jaap M Middeldorp, Jon C Aster, Fred Wang
Affiliations

Molecular evidence for rhesus lymphocryptovirus infection of epithelial cells in immunosuppressed rhesus macaques

Jeffery L Kutok et al. J Virol. 2004 Apr.

Abstract

Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with epithelial cell and B-cell malignancies. EBV infection of B lymphocytes is essential for acute and persistent EBV infection in humans; however, the role of epithelial cell infection in the normal EBV life cycle remains controversial. The rhesus lymphocryptovirus (LCV) is an EBV-related herpesvirus that naturally infects rhesus macaques and can be used experimentally to model persistent B-cell infection and B-cell lymphomagenesis. We now show that the rhesus LCV can infect epithelial cells in immunosuppressed rhesus macaques and can induce epithelial cell lesions resembling oral hairy leukoplakia in AIDS patients. Electron microscopy, immunohistochemistry, and DNA-RNA in situ hybridization were used to identify the presence of a lytic rhesus LCV infection in these proliferative, hyperkeratotic, or parakeratotic epithelial cell lesions. These studies demonstrate that the rhesus LCV has tropism for epithelial cells, in addition to B cells, and is a relevant animal model system for studying the role of epithelial cell infection in EBV pathogenesis.

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Figures

FIG. 1.
FIG. 1.
Morphological, electron microscopic, and viral phenotypic findings for a representative mucosal lesion in an SIV-infected rhesus macaque (A02-303). (A and B) Hematoxylin- and eosin-stained section of a mucosal lesion with hyperparakeratosis and prominent balloon cells within the upper epithelial cell layers. Magnifications, ×100 (A) and ×400 (B). (C) Transmission electron micrograph showing the nucleus of a degenerative mucosal epithelial cell undergoing karyolysis with marginated chromatin (long arrow) and numerous intranuclear herpesvirus nucleocapsids (short arrow). The arrowhead indicates the nuclear membrane. Bar, 200 nm. (D) Transmission electron micrograph showing an area of mucosa revealing herpesvirus virions (arrows) within the intercellular spaces between interdigitating cytoplasmic projections (arrowheads) of adjacent epithelial cells. Bar, 500 nm. The inset shows a higher magnification of virions which measure 160 nm in diameter. (E and F) Immunohistochemical staining showing expression of BZLF1 (magnification, ×400) (E) and sVCA (magnification, ×50) (F). (G and H) CISH demonstrating strong nuclear staining with a probe specific for LCV DNA. Magnifications, ×50 (G) and ×400 (H).
FIG. 2.
FIG. 2.
CISH for LCV DNA (A, C, E, G, and I) and immunohistochemical staining for sVCA (anti-sVCA-p18; BFRF3) (B, D, F, H, and J) in epithelial lesions from SIV-infected rhesus macaques A01-643 (A and B), A02-563 (C and D), A98-563 (E and F), and A99-75 (G and H) and in control nonlesional tissue from macaque A98-118 (I and J). Magnifications, ×100 (A, C, D, F, G, and H), ×50 (B and I), and ×200 (E and J).
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