Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells

Abstract

Viruses that are non- or poorly cytopathic have developed various strategies to avoid elimination by the immune system and to persist in the host. Acute infection of adult mice with the noncytopathic lymphocytic choriomeningitis virus (LCMV) normally induces a protective cytotoxic T-cell response that also causes immunopathology. But some LCMV strains (such as DOCILE (LCMV-D) or Cl-13 Armstrong (Cl-13)) derived from virus carrier mice tend to persist after acute infection of adult mice without causing lethal immunopathological disease. Tendency to persist correlates with tropism, rapidity of virus spread and virus mutations. We report here that these LCMV isolates may persist because they induce most of the specific antiviral CD8+ cytotoxic T cells so completely that they all disappear within a few days and therefore neither eliminate the virus nor cause lethal immunopathology. The results illustrate that partially and sequentially induced (protective) immunity or complete exhaustion of T-cell immunity (high zone tolerance) are quantitatively different points on the scale of immunity; some viruses exploit the latter possibility to persist in an immunocompetent host.

The enigma of CD57+CD28– T cell expansion—anergy or activation?

“…which eventually leads to the onset of AIDS (CDC stage IV) [4]. Principally this would bear some similarity with a mechanism demonstrated by Moskophidis and coworkers [13], where specific CTL activity in mice was exhausted and vanished completely following an excessive viral load, while smaller amounts of virus led to a stable increase of CTL activity (the difference between this experiment and HIV infection is obviously that in the latter the viral load increases gradually). It is doubtful that the mechanism for the final depletion of CTL in HIV infection is the loss of CD28, i.e.…”

The (gradual) rise of memory inflation

“…The situation is quite similar to that seen earlier in relation to the term immune “exhaustion”, which was first coined by Rolf Zinkernagel's team studying features of persistent lymphocytic choriomeningitis virus (LCMV) infection 7. What was seen in those studies (performed in the days before tetramers were available, but making use of transgenic models to track responses), was a loss of T‐cell reactivity and ultimately physical deletion of antiviral responses.…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…In these mice, the possibility to in vitro expand antigen-specific T-cells declines over time which led to the conclusion that a continuing infection "exhausts" or severely diminishes the pathogen-specific T-cell response 13 . The introduction of the tetramer technology and transgenic CD8 T-cells specific for an LCMV-derived antigen (P14) enabled more detailed characterizations and proved a substantial loss of effector T-cells.…”

“…A different outcome arises when infections become chronic and when viruses persist at high levels over long periods as in Human-Immunodeficiency-Virus (HIV) or Human-Hepatitis-C Virus (HCV) infections. Such conditions induce T-cells lacking the typical polyfunctional phenotype and T-cells retain the expression of inhibitory receptors including PD-1, Lag-3, Tim-3, and CD160 [9][10][11][12][13][14][15][16][17] . Very similar phenotypes can be observed, when T-cells are long-term exposed to tumor-antigen [18][19][20] .…”