Murine gammaherpesvirus 68 genes both induce and suppress lymphoproliferative disease

Abstract

Gammaherpesvirus infection is associated with an increased incidence of lymphoproliferative disease in immunocompromised hosts. Murine gammaherpesvirus 68 (gammaHV68) infection of BALB beta(2)-microglobulin-deficient (BALB beta(2)m(-/-)) mice provides an animal model for analysis of the mechanisms responsible for the induction of a lymphoproliferative disease, atypical lymphoid hyperplasia (ALH), that is pathologically similar to posttransplant lymphoproliferative disease associated with Epstein-Barr virus infection. Here we report that the gammaHV68 v-cyclin and v-bcl-2 genes are required for the efficient induction of gammaHV68-associated ALH in BALB beta(2)m(-/-) mice, while the v-GPCR gene is dispensable for ALH induction. In contrast to these findings, deletion of the viral M1 gene enhanced ALH. Thus, gammaHV68 genes can either inhibit or enhance the induction of lymphoproliferative disease in immunocompromised mice.

FIG. 1.

Splenic histology of BALB β₂m^−/− mice. (A and B) Normal; (C and D) mild follicular hyperplasia with plasmacytosis. Arrows indicate abnormal expansions of plasmacytoid cells. (E and F) ALH in a spleen from a γHV68-infected mouse. Hematoxylin and eosin staining of formaldehyde-fixed paraffin-embedded tissues. Magnifications: A, C, and E, ×40; B, D, and F, ×400.

FIG. 2.

Viral cyclin, viral bcl-2, and M1 modulate γHV68-induced lymphoproliferative disease in BALB β₂m^−/− mice. (A) BALB β₂m^−/− mice were mock infected or infected with 10⁷ PFU of wild-type γHV68 or the indicated viral mutants. At 10 months postinfection, mice were assigned to one of three splenic histopathology groups (normal, plasmacytosis, and ALH) based on splenic presentation. ND, none detected. (B to I) Spleens harvested at 10 months postinfection from BALB β₂m^−/− mice infected with the indicated viruses or from control animals (mock-infected or BL6 mouse at 16 days after γHV68 infection) were subjected to in situ hybridization using a probe against viral tRNAs. Sections were counterstained with hematoxylin, and images obtained at ×400 magnification. The spleens in panels D, E, and I displayed ALH.