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Nude mice have been shown to be as resistant to intraperitoneal infection with herpes simplex virus type 1 (HSV) as their heterozygous littermates. Here we document that both activation of natural killer (NK) cells and interferon induction were normal in nu/nu mice after injection of HSV. Injection of silica caused increased mortality by HSV in C57BL/6 mice. Silica, in addition, led to a significant reduction of NK cell activity but had no effect on the interferon response. Treatment of C57BL/6 mice with anti-asialo GM1 (an antiserum with a predominant effect on NK cells) caused complete abolition of the NK cell response, but had no effect on interferon induction or virus-induced mortality. In further studies a monoclonal anti-thy-1.2 antibody was utilized which possessed high activity in vivo in depleting T cell responses in mice. Injection of anti-thy-1.2 decreased NK cell activation but was without effect on the interferon response. Unexpectedly, in view of the data in nu/nu mice, this antibody increased HSV-induced mortality in C57BL/6 mice. Similar data were obtained when anti-thy-1.2 was injected into nu/nu mice. Our results are compatible with the hypothesis that T cell precursors sensitive to anti-thy-1.2 present in homozygous nude mice play a role in resistance against HSV. Furthermore, the data in the euthymic mice may indicate a role of T cells in the primary resistance of mice against HSV.