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Journal of Virology, January 2008, p. 382-393, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.02487-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Friend Virus Utilizes the BMP4-Dependent Stress Erythropoiesis Pathway To Induce Erythroleukemia

Aparna Subramanian,^3, Shailaja Hegde,^1,2 Prashanth Porayette,⁴ Michele Yon,^1,2 Pamela Hankey,^1,2 and Robert F. Paulson^1,2,3*

Department of Veterinary and Biomedical Sciences,¹ The Center for Molecular Immunology and Infectious Disease,² The Graduate Program in Biochemistry, Microbiology and Molecular Biology,³ Huck Institutes for the Life Sciences Molecular Medicine Option, the Pennsylvania State University, University Park, Pennsylvania⁴

Received 12 November 2006/ Accepted 3 October 2007

More than 50 years of genetic analysis has identified a number of host genes that are required for the expansion of infected cells during the progression of Friend-virus-induced erythroleukemia. In this report, we show that Friend virus induces the bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis pathway in the spleen, which rapidly amplifies target cells, propagating their infection and resulting in acute splenomegaly. This mechanism mimics the response to acute anemia, in which BMP4 expressed in the spleen drives the expansion of a specialized population of stress erythroid progenitors. Previously we demonstrated that these progenitors, termed stress BFU-E, are targets for Friend virus in the spleen (A. Subramanian, H. E. Teal, P. H. Correll, and R. F. Paulson, J. Virol. 79:14586-14594, 2005). Here, we extend those findings by showing that Friend virus infects two distinct populations of bone marrow cells. One population, when infected, differentiates into mature erythrocytes in an Epo-independent manner, while a second population migrates to the spleen after infection, where it induces BMP4 expression and acts as a reservoir of virus. The activation of the stress erythropoiesis pathway in the spleen by Friend virus results in the rapid expansion of stress BFU-E, providing abundant target cells for viral infection. These observations suggest a novel mechanism by which a virus induces a stress response pathway that amplifies target cells for the virus, leading to acute expansion of infected cells.

Published ahead of print on 17 October 2007.

Present address: Hematology-Oncology Division, David Geffen School of Medicine, UCLA, Los Angeles, CA.