Several observations suggest strongly that fever reduces virus multiplication during human viral infections. Retrospective studies have shown that the incidence and severity of paralysis among children infected with polioviruses were significantly greater in patients treated with antipyretic drugs e. Also consistent with these findings is the observation that virus strains that replicate best at fever temperature are usually virulent, whereas virus strains that replicate poorly at fever temperature are usually low in virulence and therefore often are used as live virus vaccines.
An interesting question is whether this temperature increase is important for recovery from coryza. The same general considerations of temperature probably apply to other human viral infections such as measles, rubella, and mumps, although, unfortunately, suitable and controlled studies have not been conducted.
Nevertheless, available information suggests that antipyretic drugs be used conservatively. Several antiviral mechanisms are generated by the local inflammatory response to virus-induced cell damage or to virus-stimulated mediators such as activated complement. The major components of the inflammatory process are circulatory alterations, edema, leukocyte accumulation and perhaps prostaglandins A and J. The resulting phenomena are elevated local temperature, reduced oxygen tension in the involved tissues, altered cell metabolism, and increased levels of CO 2 and organic acids.
All of these alterations, which occur in a cascading and interrelated fashion, drastically reduce the replication of many viruses. For instance, the altered energy metabolism of the infected and surrounding cells, as well as the accumulating lymphocytes, can generate local hyperthermia.
At superficial sites where the temperature is normally lower, hyperthermia can also be generated by hyperemia during the early stages of inflammation.
As inflammation progresses, hyperemia becomes passive, thereby greatly reducing blood flow and decreasing oxygen tension. Two factors account for this decrease in oxygen tension: limited influx of erythrocytes, and lower diffusion of oxygen through edema fluid. In turn, the decreased oxygen tension causes less ATP production, thus reducing the energy available for viral synthesis and increasing anaerobic glycolysis, which increases the accumulation of CO 2 and organic acids in the tissues.
These acid catabolites may decrease the local pH to levels that inhibit the replication of many viruses. Local acidity also may increase by accumulation and subsequent degradation of the leukocytes in the affected area. It is possible that other less well-defined factors are also significant.
Therefore, the local inflammation resulting from viral infection clearly activates several metabolic, physicochemical, and physiologic changes; acting individually or together, these changes interfere with virus multiplication. Although further animal and human studies are required, this interpretation is supported by the finding that anti-inflammatory drugs corticosteroids often increase the severity of infection in animals.
Therefore, these drugs should be used with caution in treating viral diseases. 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. The important role played by interferon as a defense mechanism is clearly documented by three types of experimental and clinical observations: 1 for many viral infections, a strong correlation has been established between interferon production and natural recovery; 2 inhibition of interferon production or action enhances the severity of infection; and 3 treatment with interferon protects against infection.
In addition, the interferon system is one of the earliest appearing of known host defenses, becoming operative within hours of infection. Figure 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.
Production of virus, interferon, and antibody during experimental infection of humans with influenza wild-type virus. Nonspecific defenses include anatomic barriers, inhibitors, phagocytosis, fever, inflammation, and IFN.
Specific defenses include antibody more 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, to 45, Interferons are secreted by the cell into the extracellular fluids Fig.
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. Induction of beta interferon, alpha interferon, and gamma interferon, respectively, by foreign nucleic acids, foreign cells, and foreign antigens. The three known types of interferon are induced by different stimuli. Beta interferon is induced by viral and other foreign nucleic acids in most body cells fibroblasts, epithelial cells, and macrophages.
This induction mechanism is illustrated in Figure and the top portion of Figure Cellular events of the induction, production, and action of interferon.
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 more Alpha interferon can be induced by foreign cells, virus-infected cells, tumor cells, bacterial cells, and viral envelopes that stimulate mostly circulating dendritic cells and to a lesser degree monocytes and B lymphocytes to produce it Fig. Gamma interferon is produced along with other lymphokines by T lymphocytes induced by foreign antigens to which the T lymphocytes have been presensitized Fig.
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.
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 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.
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.
Viral protein synthesis may be inhibited by several biochemical alterations of cells, which may, in theory, inhibit viral replication at the different steps shown in Figure It has been shown that the antiviral state may be transferred from interferon-treated cells to adjacent untreated cells without the continued presence of interferon Fig. 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.
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. 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. In conclusion, individual defense mechanisms assume roles of varying importance during different viral infections; in most cases, the recovery process is probably carried out by the simultaneous or sequential action of several mechanisms.
The presence of multiple defenses helps explain why suppression of one or several mechanisms does not entirely abrogate host resistance to viral infections; however, impairment of host defenses by medications used for symptomatic relief of viral infections may lead to more severe illness.
For example, aspirin and corticosteroids reduce the nonspecific defenses. Turn recording back on. National Center for Biotechnology Information , U. Show details Baron S, editor. Search term. Anatomic Barriers Anatomic barriers are located at body surfaces skin and mucosa or within the body endothelial cells and basement membranes.
Nonspecific Inhibitors Body fluids and tissues normally contain soluble viral inhibitors. Phagocytosis Viruses may be phagocytosed to different degrees by polymorphonuclear leukocytes and macrophages. Fever Replication of most viruses is reduced by even a modest rise in temperature. Inflammation Inflammation inhibits viral replication through 1 elevated local temperature, 2 reduced oxygen tension, 3 metabolic alterations, and 4 acid production.
Viral Interference and Interferon Viral interference occurs when infection by one virus renders cells resistant to the same or other superinfecting viruses. Introduction Most viral infections are limited by nonspecific defenses, which 1 restrict initial virus multiplication to manageable levels, 2 initiate recovery from established infections that is then completed by a combination of these early nonspecific and subsequent antigen-specific immune defenses, and 3 enable the host to cope with the peak numbers of virus that, if presented as the infecting dose, could be lethal.
Defense Mechanisms that Precede Infection Anatomic Barriers Anatomic barriers to viruses exist at the body surfaces and within the body. Nonspecific Inhibitors A number of viral inhibitors occur naturally in most body fluids and tissues.
Phagocytosis The limited information available suggests that phagocytosis is less effective against viral infections than against bacterial infections. Figure Possible outcomes of phagocytosis of a virus. Defense Mechanisms Evoked by Infection Fever Viral replication is influenced strongly by temperature. Figure Protection of mice by elevated temperature or antibody administered before or after intracerebral infection with the picornavirus EMC type.
Inflammation Several antiviral mechanisms are generated by the local inflammatory response to virus-induced cell damage or to virus-stimulated mediators such as activated complement. Viral Interference and Interferon Viral Interference Generally, infection by one virus renders host cells resistant to other, superinfecting viruses. Interferon The important role played by interferon as a defense mechanism is clearly documented by three types of experimental and clinical observations: 1 for many viral infections, a strong correlation has been established between interferon production and natural recovery; 2 inhibition of interferon production or action enhances the severity of infection; and 3 treatment with interferon protects against infection.
Figure Production of virus, interferon, and antibody during experimental infection of humans with influenza wild-type virus. Interferon Production and Types Interferon is produced de novo by cellular protein synthesis. Figure Induction of beta interferon, alpha interferon, and gamma interferon, respectively, by foreign nucleic acids, foreign cells, and foreign antigens.
Figure Cellular events of the induction, production, and action of interferon. Mechanism of Action Interferon does not inactivate viruses directly. Figure Molecular mechanisms of interferon antiviral actions. Interferon During Natural Infection The importance of interferon in the response to certain natural virus infections varies.
Figure Nonspecific elimination of viruses by cells. Inflammation is a nonspecific response to any trauma occurring to tissues. It is accompanied by signs and symptoms that include heat, swelling, redness, and pain. Inflammation mobilizes components of the immune system, sets into motion repair mechanisms, and encourages phagocytes to come to the area and destroy any microorganisms present.
Inflammation can be controlled by nervous stimulation and chemical substances called cytokines. These chemical products of tissue cells and blood cells are responsible for many of the actions of inflammation. The loss of fluid leads to a local swelling called edema. In some types of inflammation, phagocytes accumulate in the whitish mass of cells, bacteria, and debris called pus.
Fever is considered a nonspecific defense mechanism because it develops in response to numerous traumas. Fever is initiated by circulating substances called pyrogens , which affect the brain's hypothalamus and cause the latter to raise the temperature.
Although excessive fever can be dangerous, fever is believed to have a beneficial role because it retards the growth of temperature-sensitive microorganisms for example, leprosy bacilli , and it increases the metabolism of body cells while stimulating the immune reaction and the process of phagocytosis.
Interferon is a group of antiviral substances produced by body cells in response to the presence of viruses. Lymphocytes and macrophages produce alpha-interferon , epithelial cells produce beta-interferon , and T-lymphocytes produce gamma-interferon.
The interferons do not directly inhibit viruses. Instead, they stimulate adjacent cells to produce substances that inhibit the replication of viruses in those cells.
Interferons produced in response to one virus will protect against many other types of viruses, and for this reason, interferon is considered a nonspecific form of defense. Previous The Development of Infectious Disease.
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