The genetic basis of the control of acute splenic MCMV infection was studied after intraperitoneal inoculation of the virus. Classical Mendelian analyses using C57BL/6 (resistant) and BALB/c (susceptible) parental strains disclosed an autosomal dominant non-H-2 gene that regulates splenic virus replication. The probable location of this gene, to which we have assigned the symbol Cmv-1, is on chromosome 6 as defined by the strain distribution pattern of splenic MCMV replication in CXB recombinant inbred mice. Although there is a similar hierarchy of resistance to MCMV and HSV-1 with respect to the C57BL and BALB genetic backgrounds, the strain distribution pattern of HSV-1 replication in recombinant inbred mice suggests that Cmv-1 is not involved in restricting the spread of this virus. This is the first clear identification of a non-H-2 gene regulating the magnitude of MCMV infection. Elucidation of the function of this gene may be a fundamental step towards understanding the control of systemic CMV infection.

SummaryThe role of CD8 § T cells in resistance to herpes simplex virus (HSV) was examined. After cutaneous inoculation, HSV spreads to the peripheral nervous system (PNS) where it replicates in ganglionic neurons. In normal mice, replication of virus in the PNS was rapidly terminated and evidence of neuronal destruction, assessed by a quantitative histological assay, was sparse. Clearance of infectious virus was impaired, and a strikingly high proportion of ganglionic neurons was killed, in mice treated with an antibody that depleted them of CD8 + T cells. These results suggest that CD8 + T cells play an important role in maintaining the integrity of the sensory nervous system during primary infection with HSV. Therefore, viral epitopes recognized by CD8 + T cells and restricting class I major histocompatibility complex genes are, in principle, implicated as interacting genetic determinants of neurovirulence.

Ag-presenting molecule CD1 and CD1-restricted NKT cells are known to contribute to defense against a range of infectious pathogens, including some viruses. CD1-restricted NKT cells, a distinct subpopulation of T cells, have striking and rapid effector functions that contribute to host defense, including rapid production of IFN-γ and IL-4, and activation of NK cells. Consideration of the important contributions of innate and adaptive immunity to clearance of HSV prompted us to investigate the role of CD1 and of NKT cells expressing the Vα14-Jα281 TCR in the pathogenesis of HSV infection. To address this issue, we compared infection in wild-type mice with that in CD1 gene knockout (GKO) and Jα281 GKO mice. In this study, we report impaired clearance of virus and viral Ags, and more florid acute infection in mice lacking CD1 (and by inference, CD1-restricted T cells), in comparison with parental C57BL6 mice. In Jα281 GKO mice there was also impairment of virus clearance, resembling that seen in CD1 GKO mice. These results imply roles for the Vα14-Jα281 subset of NKT cells and for CD1d in control of HSV infection.

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