1098. How Morbilliviruses Antagonize Innate Immunity and Swiftly Inactivate the Adaptive Immune System
Authors: Veronika von Messling, Nicholas Svitek, Roberto Cattaneo
Journal: Molecular Therapy (2006)

INTRODUCTION. About 700,000 children die each year due to the consequences of measles-induced immunosuppression. The lack of a small animal model has limited studies of measles virus (MV) pathogenesis, but experimental infections of ferrets with canine distemper virus (CDV) recapitulate many immunosuppression hallmarks observed after MV infection: depression of tuberculin/DTH test responses, lowered leukocyte counts and antibody titers, and reduced in vitro lymphocyte proliferation activity. RESULTS. To analyze the viral determinants of immunosuppression we generated CDV either selectively receptor-blind or incapable of expressing either one, or both, candidate interferon antagonists proteins. Our analysis revealed striking similarities between the early phases of immunosuppression induced by morbilliviruses and HIV. A few days after inoculation, massive infection of primary and secondary lymphatic organs including intestinal Peyer's patches occurred depending on recognition of the signaling lymphocytic activation molecule (SLAM, CD150). Infection of about half the circulating lymphocytes, selective depletion of T-cells, and complete inhibition of the cytokine response followed. These events depend on V, the essential interferon antagonist and cytokine response inhibitor. An effect of the other viral protein C on the severity of rash and digestive symptoms was observed only in a V-defective genetic background. DISCUSSION. These findings reform our understanding of morbillivirus immunosuppression: we prove formally that SLAM is the primary morbillivirus receptor, that V is the essential interferon antagonist and cytokine response inhibitor, and that V is an infectivity factor. Understanding of the viral determinants of immunosuppression provides guidance for the development of measles virus-based multivalent vaccines and oncolytic vectors. INTRODUCTION. About 700,000 children die each year due to the consequences of measles-induced immunosuppression. The lack of a small animal model has limited studies of measles virus (MV) pathogenesis, but experimental infections of ferrets with canine distemper virus (CDV) recapitulate many immunosuppression hallmarks observed after MV infection: depression of tuberculin/DTH test responses, lowered leukocyte counts and antibody titers, and reduced in vitro lymphocyte proliferation activity. RESULTS. To analyze the viral determinants of immunosuppression we generated CDV either selectively receptor-blind or incapable of expressing either one, or both, candidate interferon antagonists proteins. Our analysis revealed striking similarities between the early phases of immunosuppression induced by morbilliviruses and HIV. A few days after inoculation, massive infection of primary and secondary lymphatic organs including intestinal Peyer's patches occurred depending on recognition of the signaling lymphocytic activation molecule (SLAM, CD150). Infection of about half the circulating lymphocytes, selective depletion of T-cells, and complete inhibition of the cytokine response followed. These events depend on V, the essential interferon antagonist and cytokine response inhibitor. An effect of the other viral protein C on the severity of rash and digestive symptoms was observed only in a V-defective genetic background. DISCUSSION. These findings reform our understanding of morbillivirus immunosuppression: we prove formally that SLAM is the primary morbillivirus receptor, that V is the essential interferon antagonist and cytokine response inhibitor, and that V is an infectivity factor. Understanding of the viral determinants of immunosuppression provides guidance for the development of measles virus-based multivalent vaccines and oncolytic vectors.