Virus Immunopathology

Humoral Immunity:

In addition to neutralization by antibodies, complement plays an important role in virus infections. Virolysis is the direct lysis of virus particles by antibodies plus complement.
Lachmann P.J. & Davies A. (1997) Complement and immunity to viruses.Immunol.Rev. 159:69-77.

Cell Mediated Immunity (CMI)

The Role of MHC:

T cell recognition, therefore, involves direct cell-cell contact between the antigen-specific TcR on the T lymphocyte and an MHC compatible cell which presents the processed antigen in association with surface MHC molecules. The finding that self MHC molecules are involved in the recognition of antigen by T lymphocytes led to the concept of "MHC restriction" of T cell responses, and pointed to the important role that products of the major histocompatibility complex play in the cell mediated immune response. The major histocompatibility complex consists of a cluster of genes, most of which encode products with immunologically related functions.

In humans, the MHC is located on the short arm of chromosome 6 and spans approximately four megabases of DNA. It can be divided into three regions termed class I, class II and class III:

• The class III region contains genes which encode a number of complement components and the tumour necrosis factor cytokines, amongst other molecules.
• MHC class I molecules consist of a polymorphic, MHC-encoded, membrane-spanning heavy chain, and a monomorphic light chain, β2-microglobulin.
• MHC class II molecules consist of a heterodimer of two MHC-encoded, membrane-spanning proteins, the α and β polypeptide chains of the MHC class II molecule.

In addition to the interaction between MHC/antigen and the TcR, MHC class I and class II molecules also bind to the CD8 and CD4 T cell surface molecules, respectively.

Thus, MHC class I molecules present antigen to CD8+ T cells:

Animation: Degradation and transport of antigens that bind MHC class I molecules
(needs Macromedia Shockwave Flash Player)

MHC class II molecules present antigen to CD4+ T cells:

Animation: Degradation and transport of antigens that bind MHC class II molecules
(needs Macromedia Shockwave Flash Player)

• Accessing Complexity: The Dynamics of Virus-Specific T Cell Responses. Ann.Rev.Immunol. 2000 18: 561-592.
• Successful control of viruses by NK cells-a balance of opposing forces? Trends Microbiol. 2002 10:470-442.
• Complementing viral infection: mechanisms for evading innate immunity. Trends Microbiol. 2003 11: 449-452.
• Immunological memory to viral infections. Ann Rev Immunol. 2004 22: 711-743.

• Apoptosis: Dance of Death
• Roulston, A. et al. (1999) Viruses and apoptosis. Ann. Rev. Microbiol. 53: 577-628

(adapted from: Nash, P. (1999) Immunomodulation by viruses: the myxoma virus story. Immunol.Rev. 168: 103-20)

Evasion of immune responses by viruses:

• Inhibition of MHC class I-restricted antigen presentation
• Inhibition of major histocompatibility complex class II restricted-antigen presentation
• Downregulation of CD4 by human immunodeficiency virus
• Inhibition of natural killer cell lysis
• Interference with apoptosis
• Inhibition of cytokine action
• Evasion of humoral immunity

Tortorella D. et al. (2000) Viral Subversion of the Immune System. Ann.Rev Immunol. 18: 861-926.
Orange JS, et al. Viral evasion of natural killer cells. Nat Immunol. 3: 1006-1012, 2002.
Seet B. et al. (2003) Poxviruses and Immune Evasion. Ann.Rev Immunol. 21: 377-423.

RNAi

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RNA interference (RNAi) is a mechanism where the presence of fragments of double-stranded RNA (dsRNA) interferes with the expression of a particular gene. Before RNAi was well characterized, it was called by several other names, including post transcriptional gene silencing and transgene silencing. Only after these phenomena were characterized at the molecular level was it obvious that they were the same phenomenon.

Long dsRNAs (typically >200 nt) can be used to silence the expression of target genes in a variety of organisms. On introduction to cells, the long dsRNAs enter the RNA interference (RNAi) pathway. Long dsRNAs are processed into 20-25 nt small interfering RNAs (siRNAs) by an RNase III-like enzyme called Dicer (initiation step). siRNAs assemble into endoribonuclease-containing complexes known as RNA-induced silencing complexes (RISCs), unwinding in the process. The siRNA strands guide the RISCs to complementary cellular RNA molecules, where they cleave and destroy the cellular RNA (effector step). In mammalian cells, introduction of long dsRNA (>30 nt) initiates a potent antiviral response mediated by interferons (see below), which consists of nonspecific inhibition of protein synthesis and RNA degradation. The interferon response can be bypassed, however, by the introduction or expression of siRNAs into cells, leading to specific ablation of a chosen gene. Pretreatment of mammalian cells with synthetic siRNAs against viral sequences limits infection by viruses including polio, influenza and HIV. This, coupled with the recognized role of RNAi in antiviral immunity in plants, insects and nematodes indicates that RNAi might serve an antiviral function throughout evolution. In plants and invertebrates, RNAi is a form of nucleic acid-based adaptive immunity which contrasts with but also complements the complex protein-based adaptive immunity vertebrates have evolved.

Sarnow P, et al. MicroRNAs: expression, avoidance and subversion by vertebrate viruses. Nat Rev Microbiol. 2006 4: 651-9.

Interferons:

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Mechanisms of Antiviral Activity

1. 2,5-oligo A:
   
2. 68kD RNA-activated protein kinase - PKR:
   
3. MxA Protein:

The interferon-induced MxA protein belongs to the dynamin superfamily of large GTPases and accumulates in the cytoplasm. MxA is a component of the innate antiviral response and has previously been shown to inhibit the replication of some (but not all) viruses (Human MxA protein confers resistance to double-stranded RNA viruses of two virus families. 2007 J Gen Virol 88: 1319-1323).

• Toll like receptors and viruses. Rev Med Virol. 2007 17: 35-43
• Viruses & Interferons. Annu. Rev. Microbiol. 2001, 55: 255-281
• Antiviral actions of interferons. Samuel, CE. Clin Microbiol Rev. 2001, 14: 778-780
• Search for more information on this topic

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