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.
TC, NK, cytotoxicity As described in Figs 11, 18 and 21, cytotoxic T cells ‘learn’ to recognize class I MHC antigens, and then respond to these in association with virus antigens on the cell surface. It was during the study of antiviral immunity in mice that the central role of the MHC in T-cell responses was discovered. In contrast, NK cells destroy cells with low or absent MHC, a common consequence of viral 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).
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.