Cellular immune responses in HSV and CMV infections

Abstract

The herpes simplex virus (HSV) and cytomegalovirus (CMV) are the prominent members of the Herpesviridae family collectively responsible for the majority of herpes-related morbidity and mortality in humans. These viruses are therefore the subjects of this study that was undertaken to improve our understanding of the nature of immune response and the mechanism of viral modulation leading to suppression of viral replication or evasion of the host immune response in vivo. The present study has examined the T helper responses to HSV-2 and murine CMV (MCMV) and provides new insights into the nature and the modulation of the T helper responses by these viruses in vivo. B7-1/B7-2 costimulation of T cells by antigen-presenting cells is essential for T cell activation by antigen. HSV-2 infection affects the expression of both B7-1 and B7-2 on monocytes, the key antigen presenting cells in vivo, potentially in two ways with opposing outcomes. It abrogates or diminishes the IFN-gamma-upregulation of B7-1 (in 8 out of 9 patients) and B7-2 (in 6 out of 9 patients) on monocytes. However, the infection also augments the expression of B7-1 and B7-2 on monocytes through an IFN-gamma-independent mechanism (in 9 out of 9 patients). Although the clinical significance of these opposing effects is presently unclear, these may be related to the immunological mechanism or strategy leading to recurrent disease in immunocompetent hosts. Like HSV-2, infections with MCMV in mice also led to a predominant Thl type immune response characterized by high levels of IFN-gamma and low IL-4 production. Studies with specific MCMV mutants, containing Tn3 transposon in the open reading frame of M25, M27, M43, or m09 gene, led to the identification of M43 gene that specifically suppresses IL-4 response. The Tn3 disruption of M43, but not M25, M27 or m09, gene of MCMV led to a strong IL-4 response (p = 0.0002) despite the presence of a dominant IFN-gamma response. These results provide insight into the possible role of a herpesvirus gene that can profoundly modulate the nature of T helper response in vivo. The presence of a homologous genetic element in other herpesvirus genomes may explain the dominant Th1 immune response triggered by HSV-2 and possibly other herpesviruses. The obvious importance of this finding, beyond herpesvirus immunopathogenesis, lies in the ability of M43 and homologous genes to globally modulate the nature of cytokine response in vivo and suppress Th2 cytokine-mediated diseases. (Abstract shortened by UMI.)