Virus Infection and Defensive Strategies

Immunity to viruses

Virus infection and defensive strategies

· Viruses do not have the metabolic machinery for self replication and so must infect cells in order to replicate. Some defensive strategies of the immune system are directed against free virus particles, destroying them directly or neutralising their ability to infect cells. Other strategies are directed at the infected cells, either blocking virus replication, or killing the infected cells.

Strategies directed at extra-cellular viruses

· Antibodies to virus surface antigens may block the binding of viruses to cell surface receptors, thereby neutralising the viruses. In addition, antibodies can activate complement that may damage the lipid membranes of enveloped viruses. Antibodies and complement proteins may also act as opsonins to promote the phagocytosis of viruses.

· Some viruses have evolved evasion mechanisms to protect themselves from the immune system. For example, influenza virus mutates the structure of its surface proteins (haemaggluinin and neuraminidase): this changes the antigenic nature of the virus (i.e. alters the structure of epitopes) so that antibodies specific for one influenza strain may not recognise another strain. Gradual changes in the virus due to the accumulation of point mutations is called antigenic drift. Dramatic changes due to recombination between different strains of the virus is called antigenic shift.

Strategies directed at intra-cellular viruses

· A combination of defensive mechanisms target the intra-cellular phases of virus infection. The early innate response by interferons and natural killer cells limits the growth and spread of the infection. The adaptive response by Tc cells takes longer to activate, but its high efficiency may be sufficient to clear the infection.

· Virus infection triggers the infected cells to produce and secrete type 1 interferons (IFN-a and IFN-b). These bind to receptors on neighbouring cells and trigger an anti-viral state in which these cells are resistant to virus replication. This is because interferons induce enzymes that degrade viral mRNA and that inhibit protein synthesis. Type 1 interferons also enhance expression of HLA class I, thereby making cells better targets for Tc cells, and activate natural killer cells.

· The mechanism of target cell recognition by Tc cells was considered in the session on ‘T cell-mediated immunity’. Natural killer (NK) cells are also known as large granular lymphocytes but, unlike T and B lymphocytes, they do not express clonally-distributed antigen-specific receptors.

· NK cells have two mechanisms of recognising cells as targets for killing. One involves IgG antibodies binding to native viral antigens expressed on the surface of infected cells; NK cells express Fc receptors for IgG that can then bind to the antibodies, thus attaching them to the surface of the infected cells, which they can then kill – this is termed antibody-dependent cellular cytotoxicity (ADCC). Native viral proteins to which antibodies can bind are expressed on the surface of infected cells during the assembly of enveloped viruses, in which a portion of the cell surface membrane is incorporated into the structure of the virus.

· The second mechanism whereby natural killer cells can recognise virus infected cells does not involve direct interaction with virus components, but involves the NK cells sensing changes in the infected cells’ surface constituents that are indicative of the cells being abnormal (and therefore a potential threat to the body). NK cells express a set of receptors that interact with surface constituents of other cells and this interaction triggers the killer activity of the NK cells. However, they also express another set of receptors whose interactions induce inhibitory signals that prevent target cell killing, and these inhibitory signals are normally dominant over the activation signals thereby avoiding the killing of normal cells by NK cells. The surface molecules that the NK inhibitory receptors interact with are HLA class I proteins, which are expressed by all normal cells. However, some viruses induce down-modulation of HLA class I expression by the cells they infect: this reduces their attractiveness as targets for killing by Tc cells, but makes them more likely to be killed by NK cells. Infection and inflammation may also increase the expression of the target cell surface constituents that activate NK killing activity.

· Although NK cells and Tc cells employ different mechanisms to identify virus infected cells as targets for killing, these two types of killer cell use similar mechanisms to bring about target cell destruction. There are two types of killing mechanism that the killer cells employ, both of which result in the induction of target cell apoptosis. The killer cells possess granules that contain two types of protein, which are released onto the target cell surface: the perforins polymerise to form tubular structures (similar to those formed by the C9 complement protein in the membrane attack complex). These tubes are inserted into the target cell’s surface membrane, thus effectively punching holes through which the granzymes gain entry to the target cell cytoplasm where they activate caspase enzymes that initiate the apoptosis pathways. The Tc cells also express a surface protein called Fas-ligand that interacts with Fas protein on the target cell surface: this interaction also activates the apoptosis pathways.