Viral escape mechanisms--escapology taught by viruses

Abstract

Viruses have 'studied' immunology over millions of years of coevolution with their hosts. During this ongoing education they have developed countless mechanisms to escape from the host's immune system. To illustrate the most common strategies of viral immune escape we have focused on two murine models of persistent infection, lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). LCMV is a fast replicating small RNA virus with a genome prone to mutations. Therefore, LCMV escapes from the immune system mainly by two strategies: 'speed' and 'shape change'. At the opposite extreme, MCMV is a large, complex DNA virus with a more rigid genome and thus the strategies used by LCMV are no option. However, MCMV has the coding capacity for additional genes which interfere specifically with the immune response of the host. These escape strategies have been described as 'camouflage' and 'sabotage'. Using these simple concepts we describe the spectrum of viral escapology, giving credit not only to the researchers who uncovered this fascinating area of immunology but also to the viruses themselves, who still have a few lessons to teach.

Figure 1

A simple model for understanding viral persistence.

Figure 2

(a–c) Viral dynamics and T cell responses.Viral control or escape depends on the dynamics of the CD8+ T cells responses and the virus kinetics. Three different examples and their outcomes are illustrated in this figure. a) Early and broad effector response controls virus levels and prevents ‘escape through speed’. b) Disadvantaged effector response leads to viral escape and T cell exhaustion. c) ‘Intermediate’ effector response can lead to carriage, immunopathology or clearance.

Figure 4

Overview of viral interference with MHC Class II presentation. Open arrows indicate steps interfered with by viruses (‘camouflage’ strategies). Abbreviations: CIIV – major histo-compatibility class II vesicle; α – alpha chain; β – beta chain; HCMV – human cytomegalovirus; EBV – Epstein‐Barr‐virus; HPV-E5 – human papilloma virus E5 protein;HIV-1-nef – human immunodeficiency virus 1, nef protein.

Figure 3

Overview of viral interference with MHC Class I presentation. Open arrows indicate steps interfered with by viruses (‘camouflage’ strategies). Abbreviations: β2M – beta 2-microglobulin; C – calreticulin; Erp57 – thiol oxidase reductase ERp57; HC – heavy chain; T – tapasin; TAPtransporter – TAP peptide transporter associated with antigen processing; HCMV – human cytomegalovirus; HSV – herpes simplex virus; MCMV – murine cytomegalovirus; HIV-1 – human immunodeficiency virus 1; HHV-8 – human herpes virus 8; MHV-68 – murine herpes virus 68.

Figure 5

(a–b) Viral dynamics and the immune response (humoral and cellular). a) Viral kinetics under strong cellular and antibody responses – viral control. Early efficient cellular response (CTL with T cell help) followed by neutralizing antibody response prevents mutational escape due to low viral replication rate. b) Viral kinetics during escape from sequential immune responses. A chain reaction causing a failure of all three arms of the immune system leads to mutational escape of the virus.