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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- and IFN- ). 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 downmodulation 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.
Recommended reading:
Todd I, Spickett G (2005) Lecture Notes: Immunology. 5th edition. Blackwell
Publishing. Chapter 9. OR
Todd I, Spickett G (April 2010) Lecture Notes: Immunology. 6th edition.
Wiley/Blackwell. Chapter 9.