Murine T cell immunity to primary herpes simplex virus infection: Roles for costimulation and MHC class I antigen presentation

A rapid immune response is required to resolve the primary herpes simplex virus (HSV) infection and prevent host death. Two factors that potentially affect the efficiency of this response are costimulatory signals (CSs), which augment immune activation, and the disruption of MHC class I antigen presentation by HSV, which may hinder the response.; To determine the role of the CD28/CD80--86 and CD40/CD154 CSs in the anti-HSV immune response, HSV infection was assessed in mice that had the CD28/CD80--86 or CD40/CD154 interactions disrupted either genetically or with blocking reagents (CTLA4Ig and MRI, respectively). CTLA4Ig treatment greatly reduced paralysis-free survival during primary acute HSV infection. This reflected an almost total ablation of the anti-HSV CD4+ and CD8+ T cell responses due to anergy and reduced cell numbers, respectively. Disruption of CD40/CD 154 interactions impaired survival, albeit less than that observed in CTLA4Ig-treated mice, and demonstrated reductions in the CD4+, but not CD8+ T cell responses. These two costimulatory pathways functioned in part independently, since disruption of both further impaired survival. The dependence on these CSs for the control of primary HSV infection may represent a more widespread paradigm for nonsystemic viruses, which have restricted sites of replication and which employ immunoevasive measures.; One immunoevasive measure used by HSV is the specific disruption of human MHC class I antigen presentation mediated by the HSV ICP47 protein. Determining the importance of this function during in vivo HSV infection of mice has been hindered by the observation that HSV ICP47 does not efficiently disrupt murine MHC class I antigen presentation. To circumvent this limitation of the murine HSV model, recombinant HSVs (rHSVs) were generated that replaced the HSV ICP47 gene with genes from two other herpesviruses previously shown to disrupt MHC class I antigen presentation. Human cytomegalovirus, US11 and murine cytomegalovirus m152 were each cloned into HSV-1 and shown to disrupt murine MHC class I expression and recognition by CD8+ CM Preliminary in vivo studies demonstrated that the rHSVs were less neurovirulent. We speculate that the disruption of MHC class I antigen presentation by HSV may be required for protection of infected neurons from immune-mediated damage.