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Evolution of Vesicular Stomatitis Virus in Athymic Nude Mice: Mutations Associated with Natural Killer Cell Selection

Scott B. Vandepol

Department of Biology C-016, University of California, San Diego, La Jolla, California 92093, U.S.A.

BHK-21 cells readily produce tumours in athymic nude mice, but BHK-21 cells persistently infected with wild-type vesicular stomatitis virus (VSV) do not. However, rare persistently infected virus-shedding tumours (VSV-P tumour cells) were independently derived by in vivo selection on three different occasions. Cloned viruses isolated from each of these (VSV-P virus mutants) carried mutations determining the VSV-P phenotype because they all allowed growth of virus-shedding tumours in nude mice when they were used to persistently infect normal (unselected) BHK-21 cells. Treatment of nude mice with anti-asialo-GM1 allowed BHK cells persistently infected with wild-type VSV to form tumours, and BHK cells persistently infected with VSV-P were resistant to natural killer (NK) cells in vitro; this implicates NK cells in the in vivo rejection of persistently infected tumours and in the selection of the VSV-P variant. In this paper, we have sequenced the glycoprotein (G protein), matrix (M) and non-structural (NS) proteins of three independently derived VSV-P type mutants to find mutations associated with in vivo passage of persistently infected nude mouse tumours and with resistance to NK cells. We found extensive mutation in the G protein of VSV-P but relatively few mutations in the M and NS proteins. This suggests but does not prove a role for the G protein in NK cell killing of infected cells.

Keywords: NK cells, VSV mutants, glycoprotein sequence

Present address: Department of Pathology, National Cancer Institute, Bethesda, Maryland 20205, U.S.A.

Received 3 October 1985; accepted 3 December 1985.