Non-specific defence mechanisms

Interferons are a group of serum proteins with a wide range of biological activities. Virus-infected cells produce type I interferons (IFN-alpha and IFN-beta).

Type I interferons have four principal biological actions:

  1. inhibition of viral replication;
  2. inhibition of cell proliferation;
  3. increased lytic potential of NK cells (below);
  4. modulation of MHC (histocompatibility) molecule expression on the cell surface (increased class I, decreased class II).

Interferons stimulate synthesis of several intracellular enzymes that interfere with viral RNA or DNA replication, inducing a resistant "anti-viral state".

NK ("natural killer") cells are large granular lymphocytes that do not belong to either the T or B cell lineage. They do not possess immunoglobulin or T cell receptors, CD3, CD4 or CD8 surface molecules. They kill (by cytolysis) and target:

  1. virus-infected cells;
  2. IgG coated target cells;
  3. certain types of tumour cells in vitro (the ‘in vivo’ significance of this is not yet established).

Specific defence mechanisms

Specific immunity is mediated by lymphocytes with antigen receptors. These cells are produced in the primary lymphoid organs and are replenished throughout life by differentiation from pluripotent haemopoietic stem cells. They are divided into two major families:

  1. B lymphocytes (B cells), which mature within the bone marrow and produce antibodies of various isotypes when appropriately stimulated ("humoral" immunity); and
  2. T lymphocytes (T cells), which develop in the thymus and produce a number of cell types collectively responsible for cell-mediated immunity.

Anti-viral immune responses involve both humoral (B cell) and cell-mediated (T cell) immunity. Neutralising antibodies are important during extracellular phases of the viral life-cycle. These antibodies bind to envelope or capsid proteins and prevent viral attachment and entry into host cells. Antibodies are formed during primary (and subsequent) infection and after vaccination. Secretory IgA may be important for neutralising viruses that enter via the respiratory or gastrointestinal tract. High affinity IgG antibodies in serum and extracellular fluid may prevent viraemia and cell-to-cell spread in the early stages of infection. Stimulation of high titres of neutralising antibodies is an important goal of protective vaccination.

Cytotoxic T lymphocytes (CTL) are the principal mechanism of clearance of an established viral infection. CTL are CD8+ antigen specific cells which recognise endogenously synthesised viral antigens presented on cell membrane of infected cells bound to HLA Class I molecules. The latter are expressed on all nucleated cells.

Differentiation of precursor CTL into activated effector cells requires cytokines produced by CD4+ T helper cells.

T helper cells recognise and bind to processed viral antigens associated with HLA class II molecules on the surface of antigen-presenting cells. CTL clear infecting viruses by killing the infected host cells in which they replicate. In some infections, T helper cells and CTL may contribute as much if not more to tissue injury and clinical symptoms as the virus itself does.

Immunological memory

The primary antibody response to viral infection begins within 5-7 days after exposure to the foreign antigen. Antigen-specific B cells first differentiate into IgM-secreting plasma cells. These antibodies are of relatively low binding affinity and are unable to pass out of the bloodstream into the extracellular fluid. The IgM response is of short duration. Within 10-14 days some B cells undergo class switching and begin to secrete IgG or IgA antibodies.

Class switching occurs through a process of rearrangement and splicing of immunoglobulin genes. Cytokines secreted by T helper cells are essential for class switching to occur. At the same time, somatic mutation of V-region genes and preferential clonal proliferation enables the antibody response to undergo affinity maturation with production of large amounts of high-affinity neutralising antibody. Class-switched B cells differentiate into both short-lived antibody-secreting plasma cells and longer-lived B memory cells. The latter are capable of rapid reactivation when re-exposed to viral antigens.

Compared with the primary response, this secondary antibody response is characterised by:

  1. A more rapid onset;
  2. Greater magnitude (higher antibody titre);
  3. Longer duration. Persistence of viral fragments in antigen-presenting cells within the lymphoid tissues and the presence of T helper cells enables continuing activation of B memory cells and ongoing production of neutralising antibody

Lasting T cell immunity to virus infection occurs as a result of induction of memory T cells. Primary infection stimulates not only activated T helper cells and CTL which clear the acute infection, but also induces long-lived, memory T helper cells and CTL of the same specificity.

These recirculate through lymphoid and other tissues via lymph and bloodstream. When re-exposed to the same virus, these cells are capable of rapid activation and clearance of virus, preventing recurrence of clinical disease.

Evasion of the immune response

Viruses have evolved the following mechanisms for evasion of immunological recognition and elimination:

  1. Their predominantly intracellular life-cycle protects viruses from antibodies, which cannot penetrate into the cytoplasm of living cells membranes;
  2. modulation of MHC expression or viral "latency" may impair antigen presentation and prevent T cell recognition of virus-infected host cells;
  3. some viruses may produce factors which inhibit production of cytokines such as IL-2 and IFN-gamma;
  4. induction of regulatory T cells with suppressive effects may inhibit the development of protective immunity;
  5. some viruses directly infect lymphocytes, impairing their immunological function (e.g. HIV); and
  6. many viruses are capable of extensive antigenic variation, producing serologically distinct strains against which immunological memory of past infection does not confer protection.

References

Roitt, I., Brostoff, J., Male, D., (eds.), 2001, Immunology, 6th edition, Mosby, Edinburgh; New York. Chapter 14, 'Immunity to viruses'. A similar chapter is in Roitt et al 5th edition chapter 16

Abbas, A.K., Lichtman, A.H., 2010, Cellular and molecular immunology, 6th edition Saunders, Philadelphia. Chapter 15 'Immunity to microbes'.