Generally, infection by one virus renders host cells resistant to other, superinfecting viruses. This phenomenon, called viral interference, occurs frequently in cell cultures and in animals (including humans). Although interference occurs between most viruses, it may be limited to homologous viruses under certain conditions. Some types of interference are caused by competition among different viruses for critical replicative pathways (extracellular competition for cell surface receptors, intracellular competition for biosynthetic machinery and genetic control). Similar interference may result from competition between defective (nonmultiplying) and infective viruses that may be produced concurrently. Another type of interference—the most important type in natural infections—is directed by the host cells themselves. These infected cells may respond to viral infection by producing interferon proteins, which can react with uninfected cells to render them resistant to infection by a wide variety of viruses.
Nonspecific defenses include anatomic barriers, inhibitors, phagocytosis, fever, inflammation, and IFN. Specific defenses include antibody and cell-mediated immunity. Data from a study by B. Murphy et al, National Institutes of Health (personal communication).
compares the early production of interferon with the level of antibody during experimental infection of humans with influenza virus. Clinical studies of interferon and its inducers have shown protection against certain viruses, including hepatitis B and C viruses, papovaviruses, rhinoviruses, and herpes simplex virus.
Although interferon was first recognized as an extraordinarily potent antiviral agent, it was found subsequently to affect other vital cell and body functions. For example, it may enhance killing by granulocytes, macrophages, natural killer (NK) cells, and cytotoxic lymphocytes and affect the humoral immune response and the expression of cell membrane antigens and receptors. It may also lyse or inhibit the division of certain cells, influence cell differentiation, and cross-activate hormone functions such as those of epinephrine and adrenocorticotropin (ACTH). The effect of these modulations may influence many viral infections.
Interferon is produced de novo by cellular protein synthesis. The three types (alpha, beta, and gamma) differ both structurally and antigenically and have molecular weights ranging from 16,000 to 45,000. Interferons are secreted by the cell into the extracellular fluids (Fig. 49-4
). Usually, virus-induced interferon is produced at about the same time as the viral progeny are released by the infected cell, thus protecting neighboring cells from the spreading virus.
Inducers of interferon react with cells to depress the interferon gene(s) (A). This leads to the production of mRNA for interferon (B). The mRNA is translated into the interferon protein (C), which is secreted into the extracellular fluid(D), where it reacts with the membrane receptors of cells (E). The interferon-stimulated cells derepress genes (F) for effector proteins (AVP) that establish antiviral resistance and other cell changes. The activated cells also stimulate contacted cells (G) to produce AVP by a still unknown mechanism.
and the top portion ofFigure 49-5.
, middle).
). Mitogens for T cells may mimic this induction. Gamma interferon has several unusual properties: (1 ) it exerts greater immunomodulatory activity, including activation of macrophages, than the other interferons; (2) it exerts greater lytic effects than the other interferons; (3) it potentiates the actions of other interferons; (4) it activates cells by a mechanism significantly different from that of the other interferons; and (5) it inhibits intracellular microorganisms other than viruses (e.g., rickettsia).
The 24 genes that code for interferons alpha and the single gene for beta in humans, are located in adjacent positions on chromosome 9. The only gene for interferon gamma is found on chromosome 12. The genes for interferons alpha and beta exhibit significant homology but not with interferon gamma.
Genes for interferon alpha may be differentiated into two distinct clusters on the basis of the degree of homology. As a consequence, interferon alpha comprises two families of proteins, at least 14 of which belong to the alpha-1 type and two to the alpha-2 type (omega and tau).
Also, interferon occurs without apparent stimulation in the plasma of patients with autoimmune diseases (such as rheumatoid arthritis, disseminated lupus erythematosus and pemphigus) and in patients with advanced HIV infection. In these cases, an interferon antigenically identical to interferon alpha is present but which, unlike the latter, is partially inactivated at pH 2 (acid-labile interferon alpha). This interferon is a synergistic combination of interferons alpha (acid stable) and gamma (acid labile). Consequently, acid treatment reduces the interferon activity by inactivating the synergistic interferon gamma.
Interferon does not inactivate viruses directly. Instead, it prevents viral replication in surrounding cells by reacting with specific receptors on the cell membranes to derepress cellular genes that encode intracellular effector antiviral proteins, which must be synthesized before virus replication can be inhibited (Figs. 49-5
and49-6
). Alpha and beta interferons both bind to the same type of membrane receptor; gamma interferon binds to a different receptor. The antiviral proteins probably inhibit viral multiplication by inhibiting the synthesis of essential viral proteins, but alternative or additional inhibitory mechanisms (e.g, inhibition of transcription and viral release) also occur. Viral protein synthesis may be inhibited by several biochemical alterations of cells, which may, in theory, inhibit viral replication at the different steps shown inFigure 49-6.
); this transfer mechanism may further amplify and spread the activity of the interferon system.
The interferon system is nonspecific in two ways: (1) various viral stimuli induce the same type of interferon, and (2) the same type of interferon inhibits various viruses. On the other hand, the interferon molecule is mostly specific in its action for the animal species in which it was induced: interferon produced by animals or humans generally stimulates antiviral activity only in cells of the same or closely related families (e.g., human interferon protects human and monkey cells, but not chicken cells).
The importance of interferon in the response to certain natural virus infections varies. Much depends on the effectiveness of the virus in stimulating interferon production and on its susceptibility to the antiviral action of interferon. Interferon protects solid tissues during virus infection; it is also disseminated through the bloodstream during viremia, thereby protecting distant organs against the spreading infection. Cells protected against viral replication may eliminate virus by degrading the virus genome (Fig. 49-7
).
Interferons have been approved in several nations for treatment of viral infections (papillomas and condylomata, herpes simplex, and hepatitis B and C) and cancers (hairy cell leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphomas, and Kaposi's sarcoma in AIDS patients). Clinical trials also have shown effectiveness against cryoglobulinemia and thrombocytosis and maintenance of remission in multiple myeloma. Interferon beta has received governmental approval for treatment of relapsing multiple sclerosis and interferon gamma for chronic granulomatous disease. Studies of effectiveness in other viral infections and cancers are continuing, as are studies with substances capable of inducing endogenous interferon.
