Immunity To Viruses
Viruses differ from
all other infectious
organisms in being
much smaller (see Appendix
I) and lacking cell walls and independent metabolic activity, so that they are
unable to replicate outside the cells of their host. The key process in virus
infection is therefore intracellular replication, which may or may not
lead to cell death. In the figure, viruses are depicted as hexagons, but in
fact their size and shape are extremely varied.
For rapid protection, interferon
(top) activates a large number of innate mechanisms that can block viruses
entering or replicating within cells. These molecules, collectively known as
restriction factors, have the same ‘natural antibiotic’ role as lysozyme in bacterial
infection, although the mechanisms are quite different. Antibody (right) is
valuable in preventing entry and blood-borne spread of some viruses, but is
often limited by the remarkable ability of viruses to alter their outer shape,
and thus escape detection by existing anti- body (the epidemics of influenza
that occur each year are good examples of this mechanism at work). Other
viruses escape immune surveillance by antibody by spreading from cell to cell
(left). For these viruses the burden of adaptive immunity falls to the
cytotoxic T-cell system, which specializes in recognizing MHC class I antigens
carrying viral peptides from within the
cell (see Fig. 18). However, many
viruses (such as the herpes family) have evolved ways to escape cytotoxic
T-cell recognition, by downregulating MHC expression, secreting ‘decoy’
molecules or inhibiting antigen processing. NK cells, which kill best when
there is little or no MHC on the infected cell and come into action more
rapidly than TC cells, there- fore have an important role.
Note that tissue damage may result
from either the virus itself or the host immune response to it. In the long
run, no parasite that seriously damages or kills its host can count on its own
survival, so that adaptation, which can be very rapid in viruses, generally
tends to be in the direction of decreased virulence. But infections that are
well adapted to their normal animal host can occasionally be highly virulent to
humans; rabies (dogs) and Marburg virus (monkeys) are examples of this
(‘zoonosis’).
Intermediate between viruses and
bacteria are those obligatory intracellular organisms that do possess cell
walls (Rickettsia, Chlamydia) and others without walls but
capable of extracellular replication (Mycoplasma). Immunologically, the
former are closer to viruses, the latter
to bacteria.
Receptors All viruses need to interact with specific receptors on the cell surface; examples include Epstein–Barr
virus (EBV; CR2 on cells), rabies (acetylcholine receptor on neurones), measles
(CD46 on cells) and HIV (CD4 and chemokine receptors on T cells and
macrophages).
Interferon A group of proteins (see Figs 23 and 24)
produced in response to virus infection, which stimulate cells to make proteins
that block viral transcription, and thus protect them from infection.
Antibody Specific antibody can bind to virus and thus
block its ability to bind to its specific receptor and hence infect cells. This
is called neutralization and is an important part of protection against many
viruses, including such common infections as influenza. Sometimes, viruses are
able to enter cells still bound to antibody: within the cytoplasm, a molecule
called TRIM21 binds antibody, and activates mechanisms that lead to rapid
degradation of the virus–antibody complex.
There is no proper taxonomy for
viruses, which can be classified according to size, shape, the nature of their
genome (DNA or RNA), how they spread (budding, cytolysis or directly; all are illustrated)
and – of special interest here –
whether they are eliminated or merely driven into hiding by the immune
response. Brief details of a selection of important groups of viruses are given
below.
Poxviruses (smallpox, vaccinia) Large; DNA; spread locally,
avoiding antibody, as well as in blood leucocytes; express antigens on the
infected cell, attracting CMI. The antigenic cross-reaction between these two
viruses is the basis for the use of vaccinia to protect against smallpox
(Jenner, 1798). Thanks to this vaccine, smallpox is the first disease ever to
have been eliminated from the entire globe. However, stocks of vaccine against
smallpox are once again being stockpiled in case this organism is spread
deliberately as a form of bioterrorism.
Herpesviruses (herpes simplex, varicella, EBV, CMV
[cytomegalovirus], KSHV [Kaposi sarcoma-associated herpes virus]) Medium; DNA; tend to persist and cause different symptoms
when reactivated: thus, varicella (chickenpox) reappears as zoster (shingles);
EBV (infectious mononucleosis) may initiate malignancy (Burkitt’s lymphoma; see
Fig. 42); CMV has become important as an opportunistic infection in
immunosuppressed patients; and KSHV causes Kaposi’s sarcoma in patients with
AIDS (see Fig. 28). Some herpes viruses have apparently acquired host genes
such as cytokines or Fc receptors during evolution, modifying them so as to
interfere with proper immune function.
Adenoviruses (throat and eye infections) Medium; DNA.
Numerous antigenically different types make immunity very inefficient and vaccination
a problem. However, modified adenoviruses and adeno- associated viruses are
being explored as possible gene therapy vectors, because they infect many cell
types very efficiently.
Myxoviruses (influenza, mumps, measles) Large; RNA; spread
by budding. Influenza is the classic example of attachment by specific recep-
tor (neuraminic acid) and also of antigenic variation, which limits the
usefulness of adaptive immunity. In fact the size of the yearly epidemics
of influenza can be directly related to
the extent by which each year’s virus
strain differs from its predecessor. Mumps, by spreading in the testis, can
initiate autoimmune damage. Measles infects lymphocytes and antigen-presenting
cells, causes non-specific suppression of CMI and can persist to cause SSPE
(subacute sclerosing panencephalitis); some workers feel that multiple
sclerosis may also be a disease of this type.
Rubella (‘German measles’) Medium; RNA. A mild disease
feared for its ability to damage the fetus in the first 4 months of pregnancy.
An attenuated vaccine gives good immunity.
Rabies Large; RNA. Spreads via nerves to the central
nervous system, usually following an infected dog bite. Passive antibody
combined with a vaccine can be life-saving.
Arboviruses (yellow fever, dengue) Arthropod-borne; small;
RNA. Blood spread to the liver leads to jaundice.
Enteroviruses (polio) Small; RNA. Polio enters the body via
the gut and then travels to the central nervous system where it causes
paralysis and death. Within the blood it is susceptible to antibody
neutralization, the basis for effective vaccines (see Fig. 41).
Rhinoviruses (common cold) Small; RNA. As with adenoviruses
there are too many serotypes for antibody-mediated immunity to be effective
across the whole population.
Hepatitis can be caused by at least six viruses,
including A (infective; RNA), B (serum-transmitted; DNA) and C (previously
known as ‘non-A non-B’; RNA). In hepatitis B and C, immune complexes and
autoantibodies are found, and virus persists in ‘carriers’, particularly in
tropical countries and China, where it is strongly associated with cirrhosis
and cancer of the liver. Treatment with IFNα or other antivirals can some-
times induce immunity and result in viral control. Very effective vaccines are
now available for uninfected adults against hepatitis A and B.
Arenaviruses (Lassa fever) Medium; RNA. A haemorrhagic
disease of rats, often fatal in humans. A somewhat similar zoonosis is Marburg
disease of monkeys.
Retroviruses (tumours, immune deficiency) RNA. Contain
reverse transcriptase, which allows insertion into the DNA of the infected
cell. The human T-cell leukaemia viruses (HTLV) and the AIDS virus (HIV) belong
to this group and are discussed separately (for details see Fig. 28).
Atypical organisms
Trachoma An organism of the psittacosis group (Chlamydia).
The frightful scarring of the conjunctiva may be due to over-vigorous CMI.
Typhus and other Rickettsia may survive in
macrophages, like the tubercle bacillus.
Prions These are host proteins which under certain
circumstances can be induced to polymerize spontaneously to form particles
called ‘prions’. They are found predominantly in brain, and can cause
progressive brain damage (hence their original classification as ‘slow
viruses’). The first example of a ‘prion’ disease was kuru, a fatal
brain disease spread only by cannibalism. However, prion diseases are now
thought to be responsible for scrapie and, most notoriously, for the UK
epidemic of bovine spongiform encephalopathy (BSE or ‘mad cow disease’) and the
human equivalent, Creutzfeldt–Jakob disease (CJD). Many aspects of prion
disease remain poorly understood and there is no known treatment. There appears
to be little or no immune response to
prions, perhaps because they are ‘self’ molecules.
