Viral Evasion and Deception Strategies

Viral infection involves an ongoing battle between the replicating virus and the host defense mechanism which seeks to destroy infected cells or eliminate viral replication. On the one hand, the host has developed an immune system able to attack viruses and virally infected cells, whereas, on the other hand, viruses have developed an array of immune evasion mechanisms to escape killing by the host's immune system. At present, a multiplicity of mechanisms has been described how viruses evade host immunity.

Antigenic Variation

Antigenic variation refers to the observation that different isolates of a single virus species may show variable cross-reactivity when tested with a standard serum. A primary basis of antigenic variation is a selection of virus mutants by antibodies. Escape mutants may also be selected by CD4+ or CD8+ T cells. Antigenic variation is displayed by a number of important pathogenic viruses. Compared with most DNA polymerases, RNA viruses have a higher mutation rate due to the RNA replicases that lack the proofreading capacity. The variation may be manifest in different ways depending on the virus’ natural biology. Individual strains may show antigenic drift, presumably generating new serotypes over time.

Pattern Recognition Receptor Evasion

Viruses are detected by different classes of pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and cytoplasmic DNA receptors. All PRR signaling pathways converge with the activation of IκB kinase (IKK) family members. So, direct inhibition of IKKs is an efficient viral strategy to disable multiple PRR pathways and it is used by many viruses. Viruses also actively subvert TLRs to manipulate the host cytokine environment for their benefit.

Complement Evasion

Viruses have developed different strategies to evade complement-mediated destruction. Common conserved features include secretion of proteases, complement disguise, and expression of complement inhibitors. For example, viruses protect the membranes of infected cells and the lipid envelopes of virus particles from complement lysis by encoding homologs of inhibitors of the membrane attack complex. Some herpesviruses, poxviruses, and retroviruses mimic or interact with complement regulatory proteins to block complement activation and neutralization of virus particles.

Fig.1 Complement evasion strategies of viruses. (Agrawal, 2017)

Cytokines

Viruses have evolved numerous mechanisms to evade the immune response, including proteins that target the function of cytokines.

• Molecular mimicry: viral cytokines and cytokine receptors

Viral cytokines act as agonists inducing specific immune responses that are beneficial for viruses. Viral genes encoding soluble cytokine receptors function as decoy receptors binding cytokines with high affinity and blocking their activity. Viruses modulate chemokine activity through the expression of chemokine homologues, chemokine receptor homologues, and secreted chemokine-binding proteins

• anti-IFN mechanisms

Interferon (IFN) is responsible for eliminating many viruses that otherwise will be pathogenic. Viral proteins do this either through interfering with downstream IFN pathways or through modulating IFN synthesis and degradation. The complex regulation of the IFN response allows viruses to antagonize IFN at multiple levels. For example, the transcription factors that control IFN induction, IFN-regulatory factor 3 (IRF3), IRF7, and nuclear factor-κB, are directly antagonized by viruses. Many viral proteases that participate in the cleavage and processing of viral polyproteins, typical of positive-strand RNA viruses, have also been shown to trigger the cleavage of factors essential for the IFN response.

Fig.2 Examples of viral strategies of inhibition of IFN signaling. (García-Sastre, 2017)

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References

1. Agrawal, P.; et al. Complement evasion strategies of viruses: an overview. Frontiers in microbiology. 2017, 8: 1117.
2. García-Sastre A. Ten strategies of interferon evasion by viruses. Cell host & microbe. 2017, 22(2): 176-184.

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