A few changes in wild-type picornavirus genome lead to immunosuppression (VIR8P.1068)

Abstract

Abstract Viruses, such as human immunodeficiency virus and poliovirus, use a variety of mechanisms to suppress the immune response and evade clearance by the host. Therefore, investigating how a few changes in the viral genome of a non-lethal virus can lead to an alteration in disease, from survivable to immunosuppression and death, would provide valuable information into viral pathogenesis. Here we investigate a picornavirus, the Theiler’s murine encephalomyelitis virus (TMEV), in its natural host, the mouse. C57BL/6 mice infected intracerebrally (i.c.) with the DA strain of TMEV develop acute encephalitis; mice survive the acute disease and clear the virus. A mutant of the DA strain of TMEV was inadvertently created, called H101, which encodes a point mutation (T101I) in VP1. Additional sequencing showed several nucleotide substitutions in the 5’ untranslated region as well as additional amino acid substitutions in the capsid protein coding region, suggesting that there are a number of perturbations in the viral genome. C57BL/6 mice infected with the H101 mutant via a peripheral route [intraperitoneal (i.p.)] become immunosuppressed through specific depletion of T cells. For C57BL/6 mice infected with the H101 mutant virus by either the i.c. or i.p. route, the immunosuppression is profound. This study provides experimental evidence that infection by a virus having just a few changes in the viral genome can now result in profound immunosuppression due to T cell depletion.