Infection of BALB/c Mice with a Herpes Simplex Virus Type 1 Recombinant Virus Expressing IFN-γ Driven by the LAT Promoter

Abstract

A recombinant herpes simplex virus type 1 expressing murine interferon-γ (IFN-γ) was constructed (HSV-IFN-γ) to study the effect of IFN-γ expression on HSV-1 infection of mice. HSV-IFN-γ was created by inserting the gene for murine IFN-γ under the control of the latency-associated transcript (LAT) promoter in a LAT-negative recombinant virus. ELISA analysis confirmed that the recombinant virus expressed high levels of IFN-γ in tissue culture. The recombinant HSV-IFN-γ had reduced virulence compared with the wild-type and LAT − parental strains as judged by death following ocular and ip infections in BALB/c mice. Replication of HSV-IFN-γ was wild type in tissue culture and mouse eyes. In addition, peak HSV-IFN-γ titers in mouse trigeminal ganglia (TG) and brain were similar for all viruses, although HSV-IFN-γ appeared in the TG and brains of ocularly infected mice earlier than either parental virus. Following stimulation with UV-inactivated virus, lymphocytes from HSV-IFN-γ-infected mice appeared to produce a steady level of interleukin-2 (IL-2) and IFN-γ throughout the first week of infection, while the IL-2 and IFN-γ levels in lymphocytes from wild-type and the LAT-negative parental virus, dLAT2903, varied over time. Also in contrast to lymphocytes from wild-type and dLAT2903-infected mice, lymphocytes from HSV-IFN-γ-infected mice produced no detectable IL-4. Following stimulation with recombinant IFN-γ (rIFN-γ), lymphocytes from HSV-IFN-γ-infected mice produced higher levels of IFN-γ, as compared to lymphocytes from control virus-infected mice. Finally, CTL and cell proliferation induced by HSV-IFN-γ were similar to those of both parental viruses. Thus, this report demonstrates that (i) HSV-IFN-γ had reduced neurovirulence, despite having enhanced replication in the TG of infected mice; (ii) HSV-IFN-γ did not enhance CTL activity above that seen in wild-type infected mice; and (iii) HSV-IFN-γ induced a T H1 pattern of cytokine response.