Lymphocytic choriomeningitis virus Clone 13 infection causes either persistence or acute death dependent on IFN-1, cytotoxic T lymphocytes (CTLs), and host genetics

Abstract

Understanding of T cell exhaustion and successful therapy to restore T cell function was first described using Clone (Cl) 13 variant selected from the lymphocytic choriomeningitis virus (LCMV) Armstrong (ARM) 53b parental strain. T cell exhaustion plays a pivotal role in both persistent infections and cancers of mice and humans. C57BL/6, BALB, SWR/J, A/J, 129, C3H, and all but one collaborative cross (CC) mouse strain following Cl 13 infection have immunosuppressed T cell responses, high PD-1, and viral titers leading to persistent infection and normal life spans. In contrast, the profile of FVB/N, NZB, PL/J, SL/J, and CC NZO mice challenged with Cl 13 is a robust T cell response, high titers of virus, PD-1, and Lag3 markers on T cells. These mice all die 7 to 9 d after Cl 13 infection. Death is due to enhanced pulmonary endothelial vascular permeability, pulmonary edema, collapse of alveolar air spaces, and respiratory failure. Pathogenesis involves abundant levels of Cl 13 receptor alpha-dystroglycan on endothelial cells, with high viral replication in such cells leading to immunopathologic injury. Death is aborted by blockade of interferon-1 (IFN-1) signaling or deletion of CD8 T cells.

Enhancing immunity prevents virus‐induced T‐cell‐mediated immunopathology in B cell‐deficient mice

“…2E). Thus, the immunopathological features observed in LCMV Docile-infected B −/− mice were similar to those described for PD-1-deficient mice [5] or for particular mouse strains [6,7] after LCMV clone 13 infection.…”

A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections

“…For instance, IFN is known to have both antiviral and immune suppressive effects. Our study has considered the former but not the latter, which is dominant late in infection, and which can be relieved by IFN blockade to achieve clearance of persistent infections (11)(12)(13). Finally, whereas in our minimal model CD8+ T cell exhaustion is fully reversible, recent studies have identified subsets of exhausted CD8+ T cells that cannot be reversed, especially with checkpoint inhibitors (52)(53)(54).…”

“…The quest for an understanding of the outcomes of viral infections has led, over the years, to the identification of an array of factors, including the size of the viral inoculum (5), the innate and NK cell responses (6,30), and host genetic variations (13), that can potentially influence the outcomes. Here, we argue that underlying the effects of these factors is an essential dynamical motif, comprising the key interactions between antigens and CD8 T cells, that governs the outcomes.…”

“…Variations in other factors as well as in the strengths of the interactions in our motif, which remain to be quantified, may explain the frequencies observed with other infections. Inter-host variations have been implicated in the differences in the outcomes realized with the same virus (13). In the extreme, a single outcome may be realized, such as with measles virus infection, which is nearly always cleared (50), or HIV infection, which invariably leads to persistence (51).…”

“…More recently, natural killer (NK) cells have been argued to act as rheostats tuning outcomes: NK cell depletion can change the outcome of infection with a high dose of LCMV from persistence of the virus with low levels of pathology to rapid host death (6). In other studies, regulatory T cells (8), factors contributing to CD8 T cell dysfunction (9,10), type I interferon (IFN) signalling (11,12), and, most recently, host genetics (13) have been argued to influence the outcomes of LCMV infection. A plethora of factors thus appears to be involved in determining the outcomes, and it is unclear how the interplay between these factors determines which outcome is reached.…”