Pathogenesis and Chemotherapy of Human Virus Infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Viral infections of the central nervous system (CNS) are a major cause of disease; most patients survive these infections and it not well understood why some patients have severe neurologic problems and others do not Since it is not possible to study the human CNS throughout the course of viral infection, we studied a non-lethal virus infection in the CNS of nonhuman primates (NHPs). We inoculated animals with a high dose of La Crosse virus (LACV), a bunyavirus infects neurons and causes encephalitis primarily in children, but with a very low mortality rate. We analyzed host gene expression, the types of neurons infected, and changes in the structure and function of CNS cells. A coordinated action of astrocytes, lymphocytes, microglia, and macrophages resulted in successful control of LACV infection by rapidly activating the immune response, clearing the virus from infected neurons, and terminating the immune response promptly. This limited the amount of inflammation and initiated tissue repair. A better understanding of these processes may provide new treatment opportunities to improve outcomes of viral CNS infections. Norovirus causes chronic diarrhea in some immunocompromised patients. At present there is no effective treatment for chronic norovirus infection. We followed two patients with inborn errors of immunity due to different genetic abnormalities and chronic norovirus infections who underwent hematopoietic stem cell transplantation. Both patients recovered polyfunctional norovirus-specific T cells associated with resolution of their chronic norovirus infection. In contrast, an increase in B cells or virus-specific antibody production was not observed. These findings indicate that virus-specific T cells, rather than antibody, correlates with clearance of chronic norovirus infection. We are currently studying if infusion of norovirus-specific T cells into patients with chronic norovirus infection will reduce the amount of norovirus they shed and stop their diarrhea.