Chapter 30: Pathogenesis and Control of Viral Diseases

The fundamental process of viral infection is the viral replicative cycle. The cellular response to that infection may range from no apparent effect to cytopathology with accompanying cell death to hyperplasia or cancer.

Viral disease is some harmful abnormality that results from viral infection of the host organism. Clinical disease in a host consists of overt signs and symptoms. A syndrome is a specific group of signs and symptoms. Viral infections that fail to produce any symptoms in the host are said to be inapparent (subclinical). In fact, most viral infections do not result in the production of disease (Figure 30-1).

Important principles that pertain to viral disease include the following: (1) many viral infections are subclinical; (2) the same disease syndrome may be produced by a variety of viruses; (3) the same virus may produce a variety of diseases; and (4) the outcome in any particular case is determined by both viral and host factors and is influenced by the environmental context and genetics of each.

Viral pathogenesis is the process that occurs when a virus infects a cell and causes cellular changes. Disease pathogenesis is a subset of events during an infection that results in disease manifestation in the host. A virus is pathogenic for a particular host if it can infect and cause signs of disease in that host. A strain of a certain virus is more virulent than another strain if it commonly produces more severe disease in a susceptible host. Viral virulence in intact animals is not necessarily related to cytopathogenicity for cultured cells; viruses highly cytocidal in vitro may be harmless in vivo, and, conversely, noncytocidal viruses may cause severe disease.

Important features of two general categories of acute viral diseases (local, systemic) are compared in Table 30-1.

To produce disease, viruses must enter a host, come in contact with susceptible cells, replicate, and produce cellular injury. Understanding mechanisms of viral pathogenesis at the molecular level is necessary to design effective antiviral strategies. Much of our knowledge of viral pathogenesis is based on cell culture and animal models because such systems can be readily manipulated and studied.

Steps in Viral Pathogenesis

Specific steps involved in viral pathogenesis are the following: viral entry into the host, primary viral replication, viral spread, cellular injury, host immune response, viral clearance or establishment of persistent infection, and viral shedding.

A. Entry and Primary Replication

Most viral infections are initiated when viruses attach and enter cells of one of the body surfaces—skin, respiratory tract, gastrointestinal tract, urogenital tract, or conjunctiva. The majority of these enter their hosts through the mucosa of the respiratory or gastrointestinal tract (Table 30-2). However, some viruses can be introduced directly into tissues or the bloodstream through skin wounds, needles (eg, hepatitis B and C, human immunodeficiency virus [HIV]), blood transfusions, or insect vectors (arboviruses).

After entry, the viral nucleic acid and virion-associated proteins interact with cellular macromolecules to ultimately produce new virions that are released from the host cell by shedding or cell lysis. The specific mechanisms of viral replication are highly variable and can be quite complex, relying on one or more intermediate stages of production. The released virions are then able to attach and infect other cells in the immediate vicinity, causing local spread of infection.

B. Viral Spread and Cell Tropism

Some viruses, such as influenza viruses (respiratory infections) and noroviruses (gastrointestinal infections), produce disease at the portal of entry and typically do not spread systematically. Others can spread to distant sites (eg, cytomegalovirus [CMV], HIV, rabies virus) and cause additional disease manifestations (Figure 30-2). Mechanisms of viral spread vary, but the most common route is via the bloodstream or lymphatics. The presence of virus in the blood is called viremia. Virions may be free in the plasma (eg, enteroviruses, togaviruses) or associated with particular cell types (eg, measles virus) (Table 30-3). Viruses may multiply within those cells (eg, Epstein-Barr virus [EBV] is lymphotrophic and can replicate within white blood cells as it spreads). Some viruses travel along neuronal axons to spread within the host (eg, rabies migrates to the brain, herpes simplex virus [HSV] travels to ganglia to produce latent infection).

Viruses tend to exhibit organ and cell-type specificities, or viral tropism. Tropism determines the pattern of systemic illness produced during a viral infection. As an example, hepatitis B virus has a tropism for liver hepatocytes, and hepatitis is the primary disease caused by the virus.

Tissue and cellular tropism by a given virus usually reflect the presence of specific cell surface receptors for that virus. Receptors are components of the cell surface with which a region of the viral surface (capsid or envelope) can specifically interact and initiate infection. Receptors are cell constituents that function in normal cellular metabolism but also happen to have an affinity for a particular virus. The identity of the specific cellular receptor is known for some viruses but is unknown in many cases.

The level of cell surface receptor expression and posttranslational modifications affect the ability of viruses to infect various cell types. For example, influenza virus requires cellular proteases to cleave virally encoded hemagglutinin in order to enable viruses to infect new cells, and expression of a glycolytic enzyme (neuraminidase) to release newly formed virions. Multiple rounds of viral replication will not occur in tissues that do not express the appropriate proteins.

C. Cell Injury and Clinical Illness

Destruction of virus-infected cells in the target tissues and physiologic alterations produced in the host by the tissue injury are partly responsible for the development of disease. Some tissues, such as intestinal epithelium, can rapidly regenerate and withstand extensive damage better than others, such as the brain. Some physiologic effects may result from nonlethal impairment of specialized functions of cells, such as loss of hormone production. Clinical illness from viral infection is the result of a complex series of events, and many of the factors that determine degree of illness are unknown. General symptoms associated with many viral infections, such as malaise and anorexia, may result from host response functions such as cytokine production. Clinical illness is an insensitive indicator of viral infection; inapparent infections by viruses are very common.

D. Recovery from Infection

Following a viral infection, the host will succumb, recover, or establish a chronic infection. Recovery mechanisms include both innate and adaptive immune responses. Interferon (IFN) and other cytokines, humoral and cell-mediated immunity, and possibly other host defense factors are involved. The relative importance of each component differs with the virus and the disease.

The importance of host factors in influencing the outcome of viral infections is illustrated by an incident in the 1940s in which 45,000 military personnel were inoculated with yellow fever virus vaccine that was contaminated with hepatitis B virus. Although the personnel were presumably subjected to comparable exposures, clinical hepatitis occurred in only 2% (914 cases), and of those only 4% developed serious disease. The genetic basis of host susceptibility remains to be determined for most infections.

In acute infections, recovery is associated with viral clearance and viral-specific antibody production. Establishment of a chronic infection involves complex interplay between viral and host immune factors, and the virus may enter a life-long latent state, or subsequently reactivate and cause disease months to years later.

E. Virus Shedding

The last stage in pathogenesis is the shedding of infectious virus into the environment. This is a necessary step to maintain a viral infection in populations of hosts. Shedding usually occurs from the body surfaces involved in viral entry (see Figure 30-2). Shedding occurs at different stages of disease depending on the particular agent involved. During viral shedding, an infected individual is infectious to contacts. In some viral infections, such as rabies, humans represent dead-end infections, and shedding does not occur. Two examples of the pathogenesis caused by disseminated viral infections are shown in Figure 30-3.

Host Immune Response

The outcome of viral infections reflects the interplay between viral and host factors. Nonspecific host defense mechanisms are usually elicited very soon after viral infection. The most prominent among the innate immune responses is the induction of cytokines such as IFNs (see later discussion). These responses help inhibit viral growth during the time it takes to induce specific humoral and cell-mediated immunity.

A. Innate Immune Response

The innate immune response is largely mediated by IFNs, which are host-coded proteins that are members of the large cytokine family that inhibit viral replication. They are produced very quickly (within hours) in response to viral infection or other inducers and are one of the body’s first responders in the defense against viral infection. IFNs also modulate humoral and cellular immunity and have broad cell growth regulatory activities.

There are multiple species of IFNs that fall into three general groups: designated IFN-α, IFN-β, and IFN-γ (Table 30-4). Both IFN-α and IFN-β are considered type I or viral IFNs; IFN-γ is type II or immune IFN. Infection with viruses is a potent inducer of IFN-α and IFN-β production; RNA viruses are stronger inducers of IFN than DNA viruses. IFNs also can be induced by double-stranded RNA and bacterial endotoxin. IFN-γ is not produced in response to most viruses but is induced by mitogen stimulation.

IFNs are detectable soon after viral infection in intact animals, and viral production then decreases (Figure 30-4). Antibody does not appear in the blood of the animal until several days after viral production has abated. This temporal relationship suggests that IFN plays a primary role in the nonspecific defense of the host against viral infections, as well as the fact that agammaglobulinemic individuals usually recover from primary viral infections about as well as normal people.

IFN is secreted and binds to cell receptors, where it induces an antiviral state by prompting the synthesis of other proteins that inhibit viral replication. Several pathways appear to be involved, including: (1) a dsRNA-dependent protein kinase, PKR, which phosphorylates and inactivates cellular initiation factor eIF-2 and thus prevents formation of the initiation complex needed for viral protein synthesis; (2) an oligonucleotide synthetase, 2-5A synthetase, which activates a cellular endonuclease, RNase L, which in turn degrades mRNA; (3) a phosphodiesterase, which inhibits peptide chain elongation; and (4) nitric oxide synthetase, which is induced by IFN-γ in macrophages.

Viruses display different mechanisms that block the inhibitory activities of IFNs on virus replication. Examples include specific viral proteins that block induction of expression of IFN (herpesvirus, papillomavirus, Filovirus, hepatitis C virus, rotavirus), block the activation of the key PKR protein kinase (adenovirus, herpesviruses), activate a cellular inhibitor of PKR (influenza, poliovirus), block IFN-induced signal transduction (adenovirus, herpesviruses, hepatitis B virus), or neutralize IFN-γ by acting as a soluble IFN receptor (myxoma virus).

B. Adaptive Immune Response

Both humoral and cellular components of the adaptive immune response are involved in control of viral infections. Viruses elicit a tissue response different from the response to pathogenic bacteria. Whereas polymorphonuclear leukocytes form the principal cellular response to the acute inflammation caused by pyogenic bacteria, infiltration with mononuclear cells and lymphocytes characterizes the inflammatory reaction of uncomplicated viral lesions.

Virus-encoded proteins serve as targets for the immune response. Virus-infected cells may be lysed by cytotoxic T lymphocytes as a result of recognition of viral polypeptides on the cell surface. Humoral immunity protects the host against reinfection by the same virus. Neutralizing antibody directed against capsid proteins blocks the initiation of viral infection, presumably at the stage of attachment, entry, or uncoating. Secretory IgA antibody is important in protecting against infection by viruses through the respiratory or gastrointestinal tracts.

Special characteristics of certain viruses may have profound effects on the host’s immune response. Some viruses infect and damage cells of the immune system. The most dramatic example is the human retrovirus HIV that infects T lymphocytes and destroys their ability to function, leading to acquired immunodeficiency syndrome (AIDS) (see Chapter 44).

Viruses have evolved a variety of ways that serve to suppress or evade the host immune response and thus avoid being eradicated. Often, the viral proteins involved in modulating the host response are not essential for growth of the virus in tissue culture, and their properties are realized only in pathogenesis experiments in animals. In addition to infecting cells of the immune system and abrogating their function (HIV), they may infect neurons that express little or no class I major histocompatibility complex (MHC) (herpesvirus), or they may encode immunomodulatory proteins that inhibit MHC function (adenovirus, herpesvirus) or inhibit cytokine activity (poxvirus, measles virus). Viruses may mutate and change antigenic sites on virion proteins (influenza virus, HIV) or may downregulate the level of expression of viral cell surface proteins (herpesvirus). Virus-encoded microRNAs may target specific cellular transcripts and suppress proteins integral to the host innate immune response (polyomavirus, herpesvirus).

The immune response to one virus or vaccine may exacerbate the disease caused by subsequent infection with similar strains. For example, dengue virus hemorrhagic fever can develop in persons who already have had at least one prior infection with another dengue serotype due to the intense host response to infection.

Another potential adverse effect of the immune response is the development of autoantibodies through a process known as molecular mimicry. If a viral antigen elicits antibodies that additionally recognize an antigenic determinant on a cellular protein in normal tissues, cellular injury or loss of function unrelated to viral infection might result. The host may then experience postinfectious autoimmune disease, such as Guillain-Barre syndrome associated with prior measles infection.

Viral Persistence: Chronic and Latent Virus Infections

Infections are acute when a virus first infects a susceptible host. Viral infections are usually self-limiting, but some may persist for long periods of time in the host. Long-term virus–host interaction may take several forms. Chronic infections (also called persistent infections) are those in which replicating virus can be continuously detected, often at low levels; mild or no clinical symptoms may be evident. Latent infections are those in which the virus persists in an occult (hidden or cryptic) form most of the time when no new virus is produced. There can be intermittent flare-ups of clinical disease; infectious virus can be recovered during these times. Viral sequences may be detectable by molecular techniques in tissues harboring latent infections. Inapparent or subclinical infections are those that give no overt sign of their presence.

Chronic infections occur with a number of animal viruses, and the persistence in certain instances depends on the age of the host when infected. In humans, for example, rubella virus and CMV infections acquired in utero characteristically result in viral persistence that is of limited duration, probably because of development of the immunologic capacity to react to the infection as the infant matures. Infants infected with hepatitis B virus frequently become persistently infected (chronic carriers); most carriers are asymptomatic (see Chapter 35).

Herpesviruses typically produce latent infections. HSVs enter the sensory ganglia and persist in a noninfectious state (Figure 30-5). There may be periodic reactivations during which lesions containing infectious virus appear at peripheral sites (eg, fever blisters). Chickenpox virus (varicella-zoster) also becomes latent in sensory ganglia. Recurrences are rare and occur years later, usually following the distribution of a peripheral nerve (shingles). Other members of the herpesvirus family also establish latent infections, including CMV and EBV. All may be reactivated by immunosuppression. Consequently, reactivated herpesvirus infections may be a serious complication for persons receiving immunosuppressant therapy.

Persistent viral infections play a far-reaching role in human disease. Persistent viral infections are associated with certain types of cancers in humans (see Chapter 43) as well as with progressive degenerative diseases of the CNS of humans (see Chapter 42). Examples of different types of persistent viral infections are presented in Figure 30-6.

Spongiform encephalopathies are a group of chronic, progressive, fatal infections of the CNS caused by unconventional, transmissible agents called prions (see Chapter 42). Prions are not viruses, but are proteins whose structural alterations can cause conformational changes in host proteins leading to aggregation and dysfunction, and are transmissible similar to other infectious agents. Some examples of prion” infections are scrapie in sheep, bovine spongiform encephalopathy in cattle and kuru and Creutzfeldt-Jakob disease in humans.

Overview of Acute Viral Respiratory Infections

Many types of viruses gain access to the human body via the respiratory tract, primarily in the form of aerosolized droplets or saliva. This is the most frequent means of viral entry into the host. Successful infection occurs despite normal host protective mechanisms, including the mucus covering most surfaces, ciliary action, collections of lymphoid cells, alveolar macrophages, and secretory IgA. Many infections remain localized in the respiratory tract, although some viruses produce their characteristic disease symptoms after systemic spread (eg, chickenpox, measles, rubella; see Table 30-2 and Figure 30-2).

Respiratory infections impose a heavy disease burden worldwide. Respiratory infections are the most common cause of mortality for children younger than 5 years, with diarrheal disease the second leading cause. Disease symptoms exhibited by the host depend on whether the infection is concentrated in the upper or lower respiratory tract (Table 30-5). The severity of respiratory infection can range from inapparent to overwhelming. Although definitive diagnosis requires isolation of the virus, identification of viral gene sequences, or demonstration of a rise in antibody titer, the specific viral disease can frequently be deduced by considering the major symptoms, the patient’s age, the time of year, and any pattern of illness in the community.

Overview of Viral Infections of the Gastrointestinal Tract

Many viruses initiate infection via the alimentary tract. A few agents, such as HSV and EBV, probably infect cells in the mouth. Viruses are exposed in the intestinal tract to secretory IgA and harsh elements involved in the digestion of food: acid, bile salts (detergents), and proteolytic enzymes. Consequently, viruses able to initiate infection by this route are resistant to acid and bile salts.

Acute gastroenteritis is the designation for short-term gastrointestinal disease with symptoms ranging from mild, watery diarrhea to severe febrile illness characterized by vomiting, diarrhea, and systemic manifestations. Rotaviruses, noroviruses, and caliciviruses are major causes of gastroenteritis. Infants and children are affected most often, and large outbreaks can occur, making these a significant public health concern.

Enteroviruses, coronaviruses, and adenoviruses also infect the gastrointestinal tract, but those infections are typically asymptomatic. Some enteroviruses, notably polioviruses, and hepatitis A virus are important causes of systemic disease but do not produce intestinal symptoms.

Overview of Viral Skin Infections

The keratinized epithelium of the skin is a tough barrier to the entry of viruses. However, a few viruses are able to breach this barrier and initiate infection of the host (see Table 30-2). Some obtain entry through small abrasions of the skin (poxviruses, papillomaviruses, HSVs), others are introduced by the bite of arthropod vectors (arboviruses) or infected vertebrate hosts (rabies virus, herpes B virus), and still others are injected during blood transfusions or other manipulations involving contaminated needles, such as acupuncture and tattooing (hepatitis B virus, HIV).

A few agents remain localized and produce lesions at the site of entry (eg, papillomaviruses, molluscum contagiosum), but most spread to other sites. The epidermal layer is devoid of blood vessels and nerve fibers, so viruses that infect epidermal cells tend to stay localized. Viruses that are introduced deeper into the dermis have access to blood vessels, lymphatics, dendritic cells, and macrophages and usually spread and cause systemic infections.

Many of the generalized skin rashes associated with viral infections develop because virus spreads to the skin via the bloodstream after replication at some other site. Such infections originate by another route (eg, measles virus infections occur via the respiratory tract), with hematogenous spreading to the skin and rash formation.

Lesions in viral skin rashes are designated as macules, papules, vesicles, or pustules. Macules, which are caused by local dilation of dermal blood vessels, progress to papules if edema and cellular infiltration are present in the area. Vesicles occur if the epidermis becomes focally detached, and they become pustules if an inflammatory reaction delivers polymorphonuclear leukocytes to the lesion. Ulceration and scabbing follow. Hemorrhagic and petechial rashes occur when there is more severe involvement of the dermal vessels.

Skin lesions frequently play no role in viral transmission. Infectious virus is not shed from the maculopapular rash of measles or from rashes associated with arbovirus infections. In contrast, skin lesions are important in the spread of poxviruses and HSVs. Infectious virus particles are present in high titers in the fluid of these vesiculopustular rashes, and they are able to initiate infection by direct contact with other hosts. However, even in these instances, it is believed that virions in oropharyngeal secretions may be more important to disease transmission than the skin lesions.

Overview of Viral Infections of the Central Nervous System

Viruses can gain access to the brain by two routes: by the bloodstream (hematogenous spread) and by peripheral nerve fibers (neuronal spread). Access from the blood may occur by growth through the endothelium of small cerebral vessels; by passive transport across the vascular endothelium; by passage through the choroid plexus to the cerebrospinal fluid; or by transport within infected monocytes, leukocytes, or lymphocytes. After the blood–brain barrier is breached, more extensive spread throughout the brain and spinal cord is possible. There tends to be a correlation between the level of viremia achieved by a bloodborne neurotropic virus and its neuroinvasiveness.

The other pathway to the CNS is via peripheral nerves. Virions can be taken up at sensory nerve or motor endings and be moved within axons, through endoneural spaces, or by Schwann cell infections. Herpesviruses travel in axons to be delivered to dorsal root ganglia neurons.

The routes of spread are not mutually exclusive, and a virus may use more than one method. Many viruses, including herpes-, toga-, flavi-, entero-, rhabdo-, paramyxo-, and bunyaviruses, can infect the CNS and cause meningitis, encephalitis, or both. Encephalitis caused by HSV is the most common viral cause of sporadic encephalitis in humans.

Pathologic reactions to cytocidal viral infections of the CNS include necrosis, inflammation, and phagocytosis by glial cells. The cause of symptoms in some other CNS infections, such as rabies, is unclear. The postinfectious encephalitis that occurs after measles infections (about one per 1000 cases) and more rarely after rubella infections is characterized by autoimmune demyelination without neuronal degeneration.

There are several rare neurodegenerative disorders, sometimes referred to as slow virus infections, that are uniformly fatal. Features of these infections include a long incubation period (months to years) followed by the onset of clinical illness and progressive deterioration, resulting in death in weeks to months; usually only the CNS is involved. Some of these infections, such as progressive multifocal leukoencephalopathy (JC polyomavirus) in immunocompromised hosts and subacute sclerosing panencephalitis (measles virus), are caused by typical viruses. In contrast, the subacute spongiform encephalopathies, typified by scrapie, are prion diseases. In those infections, characteristic neuropathologic changes occur, but no inflammatory or immune response is elicited.

Overview of Congenital Viral Infections

Few viruses produce disease in the human fetus. Most maternal viral infections do not result in viremia and fetal involvement. However, if the virus crosses the placenta and infection occurs in utero, serious damage may be done to the fetus.

Three principles are involved in the production of congenital defects: (1) the ability of the virus to infect the pregnant woman and be transmitted to the fetus; (2) the stage of gestation at which infection occurs; and (3) the ability of the virus to cause damage to the fetus directly (by infection of the fetus) or indirectly (by infection of the mother), resulting in an altered fetal environment (eg, fever). The sequence of events that may occur before and after viral invasion of the fetus is shown in Figure 30-7.

Rubella virus and CMV are presently the primary viruses responsible for congenital defects in humans (see Chapters 33 and 40). Congenital infections can also occur with herpes simplex, varicella-zoster, hepatitis B, measles, and mumps virus, as well as with HIV, parvovirus, and some enteroviruses (Table 30-6).

In utero infections may result in fetal death, premature birth, intrauterine growth retardation, or persistent postnatal infection. Developmental malformations, including congenital heart defects, cataracts, deafness, microcephaly, and limb hypoplasia, may result. Viral infection and multiplication may destroy rapidly replicating fetal cells or alter cell function. Lytic viruses, such as herpes simplex, may result in fetal death. Less cytolytic viruses, such as rubella, may slow the rate of cell division. If this occurs during a critical phase in organ development, structural defects and congenital anomalies may result.

Many of the same viruses can produce serious disease in newborns (see Table 30-6). Such infections may be contracted from the mother during delivery (perinatal) from contaminated genital secretions, stool, or blood. Less commonly, infections may be acquired during the first few weeks after birth (postnatal) from maternal sources, family members, hospital personnel, or blood transfusions. For example, HIV can be transmitted by the breast milk of an infected mother.

Effect of Host Age

Host age is a factor in viral pathogenicity. More severe disease is often produced in newborns. In addition to maturation of the immune response with age, there seem to be age-related changes in the susceptibility of certain cell types to viral infection. Viral infections usually can occur in all age groups but may have their major impact at different times of life. Examples include rubella, which is most serious during gestation; rotavirus, which is most serious for infants; and St. Louis encephalitis, which is most serious in elderly adults.

Diagnosis of Viral Infections

There are several different ways in which viral infections are diagnosed (Figure 30-8) (see Chapter 47). Rapid antigen detection methods use virus-specific monoclonal antibodies for detection. Nucleic acid or polymerase chain reaction (PCR) tests use specific primers and probes to detect viral nucleic acid. The PCR tests can be multiplexed, allowing detection of multiple viruses concurrently. Virus culture and serological testing for specific antibody responses are slow to provide results but are useful for epidemiologic and research studies. In the near future, nucleic acid-based technology using automated multiplexed PCR, high-density microarrays, and deep sequencing will likely change approaches to viral diagnosis. Because there are relatively few targeted antiviral therapies, knowledge of the specific infecting viral agent does not usually alter patient treatment, but it can be useful to determine the prognosis and for patient management.

Antiviral Chemotherapy

Unlike viruses, bacteria and protozoans do not rely on host cellular machinery for replication, so processes specific to these organisms provide ideal targets for the development of antibacterial and antiprotozoal drugs. Because viruses are obligate intracellular parasites, antiviral agents must be capable of selectively inhibiting viral functions without damaging the host, making the development of such drugs very difficult. Another limitation is that many rounds of virus replication occur during the incubation period and the virus has spread before symptoms appear, making drug treatment at that time relatively ineffective.

There is a need for antiviral drugs active against viruses for which vaccines are not available or not highly effective because of a multiplicity of serotypes (eg, rhinoviruses) or because of a constantly changing virus (eg, influenza, HIV). Antivirals can be used to treat established infections when vaccines would not be effective. Antivirals are needed to reduce morbidity and economic loss caused by viral infections and to treat increasing numbers of immunosuppressed patients who are at increased risk of disease.

Molecular virology studies are succeeding in identifying virus-specific functions that can serve as targets for antiviral therapy. Stages during viral infections that could be targeted include attachment of virus to host cells, uncoating of the viral genome, viral nucleic acid synthesis, translation of viral proteins, and assembly and release of progeny virus particles. It has been very difficult to develop antivirals that can distinguish viral from host replicative processes, but there have been successful drugs developed, particularly for chronic infections (eg, HIV, hepatitis C). A number of compounds have been developed that are of value in treatment of viral diseases (Table 30-7). The mechanisms of action vary among antivirals, and can target a viral protein enzymatic activity or block host–virus protein interaction. Some drugs must be activated by enzymes in the cell before it can act as an inhibitor of viral replication; the most selective drugs are activated by a virus-encoded enzyme in the infected cell.

Future work is necessary to minimize the emergence of drug-resistant variant viruses, to reduce drug toxicities, to design more specific antivirals based on molecular insights into the structure of other viral targets, and to develop antivirals for viruses for which no drugs currently exist.

A. Nucleoside and Nucleotide Analogs

The majority of available antiviral agents are nucleoside analogs. They inhibit nucleic acid replication by inhibition of viral polymerases essential for nucleic acid replication. In addition, some analogs are incorporated into the nucleic acid as chain terminators and block further synthesis.

Analogs can inhibit cellular enzymes as well as virus-encoded enzymes. The most effective analogs are those that are able to specifically inhibit virus-encoded enzymes, with minimal inhibition of analogous host cell enzymes. Because of high mutation rates, virus variants resistant to the drug usually arise over time, sometimes quite rapidly. The use of combinations of antiviral drugs can delay the emergence of resistant variants (eg, “triple-drug” therapy used to treat HIV infections).

B. Reverse Transcriptase Inhibitors

Nonnucleoside reverse transcriptase inhibitors act by binding directly to virally encoded reverse transcriptase and inhibiting its activity. However, resistant mutants emerge rapidly, making it useful only in the context of multidrug therapy.

C. Protease Inhibitors

Protease inhibitors were first designed by computer modeling as peptidomimetic agents that fit into the active site of the HIV protease enzyme. Such drugs inhibit the viral protease that is required at the late stage of the replicative cycle to cleave the viral gag and gag-pol polypeptide precursors to form the mature virion core and activate the reverse transcriptase that will be used in the next round of infection. Protease inhibitors have been used successfully for treatment of HIV and HCV infections.

D. Integrase Inhibitors

HIV integrase inhibitors block the activity of viral integrase, a key enzyme in HIV replication. Without integration of virally encoded DNA into the host chromosome, the life cycle cannot continue. Raltegravir was the first integrase inhibitor to be approved in 2007.

E. Fusion Inhibitors

HIV fusion inhibitors act by disrupting the fusion of viral envelope with the cell membrane, preventing cellular infection. The prototype agent, enfuvirtide, is a peptide that binds to gp41 and blocks the required conformational change that initiates membrane fusion.

D. Other Types of Antiviral Agents

A number of other types of compounds have been shown to possess some antiviral activity under certain conditions.

Amantadine and rimantadine specifically inhibit influenza A viruses by blocking viral uncoating. They must be administered very early in infection to have a significant effect.

Oseltamivir is a neuraminidase inhibitor that prevents the release of influenza virus particles from infected cells.

Foscarnet (phosphonoformic acid) is an organic analog of inorganic pyrophosphate. It selectively inhibits viral DNA polymerases and reverse transcriptases at the pyrophosphate-binding site.

Acyclovir is a guanosine analog DNA polymerase inhibitor used for the treatment of HSV and varicella-zoster virus infections. The prodrug valacyclovir is an esterified version that can be taken orally and is metabolized to acyclovir.

Ganciclovir is a nucleoside DNA polymerase inhibitor active against CMV whose specificity comes from phosphorylation by virus-specific kinases only in virally infected cells. Valganciclovir is the orally available prodrug for ganciclovir.

Viral Vaccines

The purpose of viral vaccines is to use the adaptive immune response of the host to prevent viral disease. Several vaccines have proved to be remarkably effective at reducing the incidence of viral disease (Figure 30-9). Vaccination is the most cost-effective method of prevention of serious viral infections.

A. General Principles

Immunity to viral infection is based on the development of an immune response to specific antigens located on the surface of virus particles or virus-infected cells. For enveloped viruses, the important antigens are the surface glycoproteins. Although infected animals may develop antibodies against virion core proteins or nonstructural proteins involved in viral replication, that immune response is believed to play little or no role in the development of resistance to infection.

Vaccines are available for the prevention of several significant human diseases. Currently available vaccines (Table 30-8) are described in detail in the chapters dealing with specific virus families and diseases.

The pathogenesis of a particular viral infection influences the objectives of immunoprophylaxis. Mucosal immunity (local IgA) is important in resistance to infection by viruses that replicate in mucosal membranes (rhinoviruses, influenza viruses, rotaviruses) or invade through the mucosa (papillomavirus). Viruses that have a viremic mode of spread (polio, hepatitis A and B, yellow fever, varicella, mumps, measles) are controlled by serum IgG antibodies. Cell-mediated immunity also is involved in protection against systemic infections (measles, herpes).

Certain characteristics of a virus or of a viral disease may complicate the generation of an effective vaccine. The existence of many serotypes, as with rhinoviruses, and of large numbers of antigenic variants in animal reservoirs, as with influenza virus, makes vaccine production difficult. Other hurdles include the integration of viral DNA into host chromosomal DNA (retroviruses) and infection of cells of the host’s immune system (HIV).

B. Killed-Virus Vaccines

Inactivated (killed-virus) vaccines are made by purifying viral preparations to a certain extent and then inactivating viral infectivity in a way that does minimal damage to the viral structural proteins; mild formalin treatment is frequently used (Table 30-9). For some diseases, killed-virus vaccines are currently the only ones available.

Killed-virus vaccines prepared from whole virions generally stimulate the development of circulating antibody against the coat proteins of the virus, conferring some degree of resistance to that virus strain.

Advantages of inactivated vaccines are that there is no reversion to virulence by the vaccine virus and that vaccines can be made when no acceptable attenuated virus is available. Disadvantages of killed-virus vaccines include relatively brief immunity requiring boosting shots to maintain effectiveness, poor cell-mediated response, and occasional hypersensitivity to subsequent infection.

C. Attenuated Live-Virus Vaccines

Live-virus vaccines use virus mutants that antigenically overlap with wild-type virus but are restricted in some step in the pathogenesis of disease (see Table 30-9).

The genetic basis for the attenuation of most viral vaccines is not known because they were selected empirically by serial passages in animals or cell cultures (usually from a species different from the natural host). As more is learned about viral genes involved in disease pathogenesis, attenuated candidate vaccine viruses can be engineered in the laboratory.

Attenuated live-virus vaccines have the advantage of acting more like the natural infection with regard to their effect on immunity. They multiply in the host and tend to stimulate longer-lasting antibody production, induce a good cell-mediated response, and induce antibody production and resistance at the portal of entry (Figure 30-10). Disadvantages of attenuated live-virus vaccines include a risk of reversion to greater virulence, severe infection in immunocompromised hosts, and limited storage and shelf life in some cases. Additionally, unrecognized adventitious agents have been found in vaccine stocks (eg, simian polyomavirus SV40, porcine circovirus).

D. Proper Use of Vaccines

An effective vaccine does not protect against disease until it is administered in the proper dosage to susceptible individuals. Failure to reach all sectors of the population with complete courses of immunization is reflected in the continued occurrence of measles outbreaks in populations who refuse immunization. Herd immunity refers to the fact that the risk of infection among susceptible individuals in a population is reduced by the presence of adequate numbers of immune individuals. This effect is reflected in dramatic decreases in the incidence of disease, even when all susceptible individuals have not been vaccinated. However, the threshold of immunity needed for this indirect protective effect depends on many factors, including the transmissibility of the infectious agent, the nature of the vaccine-induced immunity, and the distribution of the immune individuals. Individuals protected by herd immunity remain susceptible to infection upon exposure. This can lead to outbreaks of disease when a group of susceptible individuals accumulate, such as mumps outbreaks among university students in the United States.

Certain viral vaccines are recommended for use by the general public. Other vaccines are recommended only for use by persons at special risk because of occupation, travel, or lifestyle. In general, live-virus vaccines are contraindicated for pregnant women and immunocompromised individuals.

E. Future Vaccine Prospects

Molecular biology and modern technologies are combining to allow novel approaches to vaccine development. Many of these approaches avoid the incorporation of viral nucleic acid in the final product, improving vaccine safety. Examples of what is ongoing in this field can be listed as follows. The ultimate success of these new approaches remains to be determined.

1. Use of recombinant DNA techniques to insert the gene coding for the protein of interest into the genome of an avirulent virus that can be administered as the vaccine (eg, vaccinia virus).

2. Including in the vaccine only those subviral components needed to stimulate protective antibody, thus minimizing the occurrence of adverse reactions to the vaccine.

3. Use of purified proteins isolated from purified virus or synthesized from cloned genes (a recombinant hepatitis B virus vaccine contains viral proteins synthesized in yeast cells). Expression of cloned gene(s) sometimes results in formation of empty virus-like particles.

4. Use of synthetic peptides that correspond to antigenic determinants on a viral protein, thus avoiding any possibility of reversion to virulence since no viral nucleic acid would be present, although the immune response induced by synthetic peptides is considerably weaker than that induced by intact protein.

5. Development of edible vaccines whereby transgenic plants synthesizing antigens from pathogenic viruses may provide new cost-effective ways of delivering vaccines.

6. Use of naked DNA vaccines—potentially simple, cheap, and safe—in which recombinant plasmids carrying the gene for the protein of interest are injected into hosts and the DNA produces the immunizing protein.

7. Administration of vaccine locally to stimulate antibody at the portal of entry (eg, aerosol vaccines for respiratory disease viruses).

• Viral pathogenesis is the process when a virus infects a host.

• Most viruses enter their hosts through the respiratory or gastrointestinal tract.

• Most viral infections are inapparent and do not result in clinical disease.

• Most viral infections are self-limiting and are cleared by the host, but some lead to chronic (persistent) long-term infections.

• Both innate and adaptive immune responses (both humoral and cellular components) are important in recovery from viral infections.

• Interferons are cytokines that are central to the antiviral innate immune response of the host.

• Both viral and host factors determine the outcome of viral infections.

• Some viruses cause localized infections at the primary site of entry; other viruses spread and produce disease at distant sites in the body.

• A few viruses can infect the fetus in utero and may cause serious damage, leading to fetal death or congenital defects.

• Effective antiviral drugs must selectively inhibit viral functions and not cell processes.

• Viral vaccines are the most effective method for preventing viral infections; vaccines are available against several serious viral diseases.

• Both killed-virus and live-virus vaccines are available; each type has certain advantages and disadvantages.

• New technologies and research are enabling antiviral drug development and novel vaccine approaches.