There is evidence for natural resistance to some viruses in certain species, which is probably based on the absence of receptors on the cells of the resistant species. For example, some people are resistant to HIV infection because they lack one of the chemokine receptors that mediate entry of the virus into the cell. However, by far, the most important type of defense is acquired immunity, either actively acquired by exposure to the virus or passively acquired by the transfer of immune serum. Active immunity can be elicited by contracting the actual disease, by having an inapparent infection, or by being vaccinated.
Active immunity, in the form of both antibodies and cytotoxic T cells, is very important in the prevention of viral diseases. The first exposure to a virus, whether it causes an inapparent infection or symptomatic disease, stimulates the production of antibodies and the activation of cytotoxic T cells. The role that antibodies and cytotoxic T cells play in the recovery from this first infection is uncertain and may vary from virus to virus, but it is clear that they play an essential role in protecting against disease when exposed to the same virus at some time in the future.
The duration of protection varies; disseminated viral infections such as measles and mumps confer lifelong immunity against recurrences, but localized infections such as the common cold usually impart only a brief immunity of several months. IgA confers protection against viruses that enter through the respiratory and gastrointestinal mucosa, and IgM and IgG protect against viruses that enter or are spread through the blood. The lifelong protection against systemic viral infections such as the childhood diseases measles, mumps, rubella, and chickenpox (varicella) is a function of the anamnestic (secondary) response of IgG. For certain respiratory viruses such as parainfluenza and respiratory syncytial viruses, the IgA titer in respiratory secretions correlates with protection, whereas the IgG titer does not. Unfortunately, protection by IgA against most respiratory tract viruses usually lasts less than 5 years.
The role of active immunity in recovery from a viral infection is uncertain. Because recovery usually precedes the appearance of detectable humoral antibody, immunoglobulins may not be important. Also, children with agammaglobulinemia recover from measles infections normally and can be immunized against measles successfully, indicating that cell-mediated immunity plays an important role. This is supported by the observation that children with congenital T-cell deficiency are vulnerable to severe infections with measles virus and herpesviruses. T cells are important in recovery from many but not all viral illnesses.
The protection offered by active immunity can be affected by the phenomenon of original antigenic sin. This term refers to the observation that when a person is exposed to a virus that cross-reacts with another virus to which that individual was previously exposed, more antibody may be produced against the original virus than against the current one. It appears that the immunologic memory cells can respond to the original antigenic exposure to a greater extent than to the subsequent one. This was observed in people with antibodies to the A1 type of influenza virus, who, when exposed to the A2 type, produced large amounts of antibody to A1 but very little antibody to the A2 virus. It is also the underlying cause of severe hemorrhagic dengue fever (see Chapter 42). This phenomenon has two practical consequences as well: (1) attempts to vaccinate people against the different influenza virus strains may be less effective than expected and (2) epidemiologic studies based on measurement of antibody titers may yield misleading results.
How does antibody inhibit viruses? There are two main mechanisms. The first is neutralization of the infectivity of the virus by antibody binding to the proteins on the outer surface of the virus. This binding has two effects: (1) It can prevent the interaction of the virus with cell receptors and (2) it can cross-link the viral proteins and stabilize the virus so that uncoating does not occur. As a result, the virus cannot replicate.
Furthermore, antibody-coated virus is more rapidly phagocytized than normal virus, a process similar to the opsonizing effect of antibody on bacteria. Antibody does not degrade the virus particle; fully infectious virus can be recovered by dissociating the virus–antibody complex. Incomplete, also called “blocking,” antibody can interfere with neutralization and form immune complexes, which are important in the pathogenesis of certain diseases. Some viruses, such as herpesviruses, can spread from cell to cell across intercellular bridges, eluding the neutralizing effect of antibody.
Antibodies that interfere with the adherence (adsorption and penetration) of viruses to cell surfaces are called neutralizing antibodies. Note that neutralizing antibody is directed against the surface proteins of the virus, typically the proteins involved with the interaction of the virus with receptors on the surface of the host cell. Antibodies formed against internal components of the virus (e.g., the core antigen of hepatitis B virus) do not neutralize the infectivity of the virus.
The second main mechanism is the lysis of virus-infected cells in the presence of antibody and complement. Antibody binds to new virus-specific antigens on the cell surface and then binds complement, which enzymatically degrades the cell membrane. Because the cell is killed before the full yield of virus is produced, the spread of virus is significantly reduced.
Lysis of virus-infected cells is also caused by cytotoxic T lymphocytes. These CD8-positive T cells recognize viral antigen only when it is presented in association with class I MHC proteins (see Chapter 58). They kill virus-infected cells by three methods: (1) by releasing perforins, which make holes in the cell membrane of the infected cells; (2) by releasing proteolytic enzymes called granzymes into the infected cell, which degrade the cell contents; and (3) by activating the FAS protein, which causes programmed cell death (apoptosis).
Not all virus infections induce antibodies. Tolerance to viral antigens can occur when the virus infection develops in a fetus or newborn infant. The model system in which tolerance has been demonstrated is lymphocytic choriomeningitis (LCM) infection in mice. If LCM virus is inoculated into a newborn mouse, the virus replicates widely, but no antibodies are formed during the lifetime of the animal. The virus is recognized as “self,” because it was present at the time of maturation of the immune system. If LCM virus is given to an adult mouse, antibodies are formed normally. There is no example of total tolerance to a virus in humans; even in congenital rubella syndrome, in which the virus infects the fetus, some antibody against rubella virus is made. However, virus production and shedding can go on for months or years.
Suppression of the cell-mediated response can occur during infection by certain viruses. The best-known example is the loss of tuberculin skin test reactivity during measles infection. Infection by cytomegalovirus or HIV can also cause suppression. Some viruses can “downregulate” (reduce) the amount of class I and class II MHC protein made by cells, which may be a mechanism by which these viruses suppress cell-mediated immunity.
Transfer of human serum containing the appropriate antibodies provides prompt short-term immunity for individuals exposed to certain viruses. The term passive refers to the administration of preformed antibodies. Two types of immune globulin preparations are used for this purpose. One has a high titer of antibody against a specific virus, and the other is a pooled sample from plasma donors that contains a heterogeneous mixture of antibodies with lower titers. The immune globulins are prepared by alcohol fractionation, which removes any viruses in the serum. The three most frequently used high-titer preparations are used after exposure to hepatitis B, rabies, and varicella-zoster viruses. Low-titer immune globulin is used mainly to prevent hepatitis A in people traveling to areas where this infection is hyperendemic.
Two specialized examples of passive immunity include the transfer of IgG from mother to fetus across the placenta and the transfer of IgA from mother to newborn in colostrum.
“Herd immunity” (also known as “community immunity”) is the protection of an individual from infection by virtue of the other members of the population (the herd) being incapable of transmitting the virus to that individual (Figure 33–3). Herd immunity can be achieved by immunizing a population with a vaccine that interrupts transmission, such as the live, attenuated polio vaccine, but not with a vaccine that does not interrupt transmission, such as the killed polio vaccine (even though it protects the immunized individual against disease). Note that herd immunity occurs with the live polio vaccine primarily because it induces secretory IgA in the gut, which inhibits infection by virulent virus, thereby preventing its transmission to others. In addition, the live virus in the vaccine can replicate in the immunized person and spread to other members of the population, thereby increasing the number of people protected. However, the important feature as far as herd immunity is concerned is the induction of IgA, which prevents transmission.
Herd immunity. Immunization of the nine people (tan color) can protect the one unimmunized person (red color) by interrupting transmission. Immunization levels of 90% are generally regarded as sufficient to protect the unimmunized individual.
Herd immunity can be achieved by natural infection as well as vaccines. For example, if a viral disease, such as measles, occurred in approximately 90% of a group, and if those who recovered from the disease had sufficient immunity to prevent them from becoming infected and serving as a source of virus for others, then the remaining 10% of the group are protected by herd immunity.
Other Nonspecific Defenses
Viruses and double-stranded RNA are the most potent inducers of interferons. Many viruses induce interferons, and many viruses are inhibited by interferons (i.e., neither the induction of interferons nor its action is specific).
Interferons act by binding to a receptor on the cell surface that signals the cell to synthesize ribonuclease, protein kinase, and oligo A synthetase in an inactive form. Double-stranded RNA made by the infecting virus activates these proteins. Interferons do not enter the cell and have no effect on extracellular viruses.
Interferons inhibit virus replication by blocking protein synthesis, primarily by degrading mRNA and by inactivating elongation factor-2.
Alpha and beta interferons have a stronger antiviral action than gamma interferon. The latter acts primarily as an interleukin that activates macrophages.
Natural killer (NK) cells are lymphocytes that destroy cells infected by many different viruses (i.e., they are nonspecific). NK cells do not have an antigen receptor on their surface, unlike T and B lymphocytes. Rather, NK cells recognize and destroy cells that do not display class I MHC proteins on the surface. They kill cells by the same mechanisms as do cytotoxic T cells (i.e., by secreting perforins and granzymes).
Phagocytosis by macrophages and the clearance of mucus by the cilia of the respiratory tract are also important defenses. Damage to these defenses predisposes to viral infection.
Increased corticosteroid levels suppress various host defenses and predispose to severe viral infections, especially disseminated herpesvirus infections. Malnutrition predisposes to severe measles infections in developing countries. The very young and the very old have more severe viral infections.
Active immunity to viral infection is mediated by both antibodies and cytotoxic T cells. It can be elicited either by exposure to the virus or by immunization with a viral vaccine.
Passive immunity consists of antibodies preformed in another person or animal.
The duration of active immunity is much longer than that of passive immunity. Active immunity is measured in years, whereas passive immunity lasts a few weeks to a few months.
Passive immunity is effective immediately, whereas it takes active immunity 7 to 10 days in the primary response (or 3–5 days in the secondary response) to stimulate detectable amounts of antibody.
Herd immunity is the protection of an individual that results from immunity in many other members of the population (the herd) that interrupts transmission of the virus to the individual. Herd immunity can be achieved either by immunization or by natural infection of a sufficiently high percentage of the population.