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30 C H A P T E R Pathogenesis and Cont...

30 C H A P T E R Pathogenesis and Control of Viral Diseases PRINCIPLES OF VIRAL DISEASES based on cell culture and animal models because such sys- tems can be readily manipulated and studied. The fundamental process of viral infection is the viral repli- cative cycle. The cellular response to that infection may range from no apparent effect to cytopathology with accompanying Steps in Viral Pathogenesis cell death to hyperplasia or cancer. Specific steps involved in viral pathogenesis are the follow- Viral disease is some harmful abnormality that results ing: viral entry into the host, primary viral replication, viral from viral infection of the host organism. Clinical disease spread, cellular injury, host immune response, viral clearance in a host consists of overt signs and symptoms. A syndrome or establishment of persistent infection, and viral shedding. is a specific group of signs and symptoms. Viral infections that fail to produce any symptoms in the host are said to be A. Entry and Primary Replication inapparent (subclinical). In fact, most viral infections do not Most viral infections are initiated when viruses attach and result in the production of disease (Figure 30-1). enter cells of one of the body surfaces—skin, respiratory Important principles that pertain to viral disease include tract, gastrointestinal tract, urogenital tract, or conjunctiva. the following: (1) many viral infections are subclinical; The majority of these enter their hosts through the mucosa (2) the same disease syndrome may be produced by a variety of the respiratory or gastrointestinal tract (Table 30-2). How- of viruses; (3) the same virus may produce a variety of dis- ever, some viruses can be introduced directly into tissues or eases; and (4) the outcome in any particular case is deter- the bloodstream through skin wounds, needles (eg, hepatitis mined by both viral and host factors and is influenced by the B and C and human immunodeficiency virus [HIV]), blood environmental context and genetics of each. transfusions, or insect vectors (arboviruses). Viral pathogenesis is the process that occurs when After entry, the viral nucleic acid and virion-associated a virus infects a cell and causes cellular changes. Disease proteins interact with cellular macromolecules to ultimately pathogenesis is a subset of events during an infection that produce new virions that are released from the host cell by results in disease manifestation in the host. A virus is patho- shedding or cell lysis. The specific mechanisms of viral rep- genic for a particular host if it can infect and cause signs of lication are highly variable and can be quite complex, rely- disease in that host. A strain of a certain virus is more viru- ing on one or more intermediate stages of production. The lent than another strain if it commonly produces more severe released virions are then able to attach and infect other cells disease in a susceptible host. Viral virulence in intact animals in the immediate vicinity, causing local spread of infection. 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 B. Viral Spread and Cell Tropism disease. Some viruses, such as influenza viruses (respiratory infections) Important features of two general categories of acute and noroviruses (gastrointestinal infections), produce disease viral diseases (local, systemic) are compared in Table 30-1. at the portal of entry and typically do not spread systemati- cally. Others can spread to distant sites (eg, cytomegalovirus [CMV], HIV, and rabies virus) and cause additional disease PATHOGENESIS OF VIRAL DISEASES manifestations (Figure 30-2). Mechanisms of viral spread vary, but the most common route is via the bloodstream or To produce disease, viruses must enter a host, come in con- lymphatics. The presence of virus in the blood is called vire- tact with susceptible cells, replicate, and produce cellular mia. Virions may be free in the plasma (eg, enteroviruses injury. Understanding mechanisms of viral pathogenesis at and togaviruses) or associated with particular cell types (eg, the molecular level is necessary to design effective antiviral measles virus) (Table 30-3). Viruses may multiply within those strategies. Much of our knowledge of viral pathogenesis is cells (eg, Epstein-Barr virus [EBV] is lymphotrophic and can 437 Riedel_CH30_p437-p456.indd 437 05/04/19 4:48 PM  438   SECTION IV  Virology Cell response Host response Lysis of cell Death of organism Discernible effect Classic and Clinical disease Inclusion body formation severe disease or Cell transformation or Cell dysfunction Moderate severity Mild illness Viral multiplication Infection without without visible change clinical illness Below visual change Subclinical disease or incomplete (asymptomatic viral maturation infection) Exposure without Exposure attachment or without cell entry infection Iceberg concept of infection FIGURE 30-1 Types of host and cellular responses to virus infection. (Modified with permission from Evans AS: Epidemiological concepts. In Evans AS, Brachman PS [editors]: Bacterial Infections of Humans, 3rd ed. Plenum, 1998. With kind permission of Springer Science+Business Media.) replicate within white blood cells as it spreads). Some viruses identity of the specific cellular receptor is known for some travel along neuronal axons to spread within the host (eg, viruses but is unknown in many cases. rabies migrates to the brain, herpes simplex virus [HSV] trav- The level of cell surface receptor expression and post- els to ganglia to produce latent infection). translational modifications affect the ability of viruses to Viruses tend to exhibit organ and cell-type specificities, infect various cell types. For example, influenza virus requires or viral tropism. Tropism determines the pattern of systemic cellular proteases to cleave virally encoded hemagglutinin in illness produced during a viral infection. As an example, hep- order to enable viruses to infect new cells, and expression of atitis B virus has a tropism for liver hepatocytes, and hepatitis a glycolytic enzyme (neuraminidase) to release newly formed is the primary disease caused by the virus. virions. Multiple rounds of viral replication will not occur in Tissue and cellular tropism by a given virus usually tissues that do not express the appropriate proteins. reflect the presence of specific cell surface receptors for that virus. Receptors are components of the cell surface with C. Cell Injury and Clinical Illness which a region of the viral surface (capsid or envelope) can Destruction of virus-infected cells in the target tissues and phys- specifically interact and initiate infection. Receptors are cell iologic alterations produced in the host by the tissue injury are constituents that function in normal cellular metabolism but partly responsible for the development of disease. Some tissues, also happen to have an affinity for a particular virus. The such as intestinal epithelium, can rapidly regenerate and with- stand extensive damage better than others, such as the brain. TABLE 30-1 Important Features of Acute Viral Diseases Some physiologic effects may result from nonlethal impairment of specialized functions of cells, such as loss of hormone pro- Local Systemic Infections Infections duction. Clinical illness from viral infection is the result of a complex series of events, and many of the factors that determine Specific disease example Influenza Measles degree of illness are unknown. General symptoms associated Site of pathology Portal of entry Distant site with many viral infections, such as malaise and anorexia, may Incubation period Relatively short Relatively long result from host response functions such as cytokine produc- tion. Clinical illness is an insensitive indicator of viral infection; Viremia Absent Present inapparent infections by viruses are very common. Duration of immunity Variable—may Usually lifelong be short D. Recovery from Infection Role of secretory antibody Usually Usually not Following a viral infection, the host will succumb, recover, or (IgA) in resistance important important establish a chronic infection. Recovery mechanisms include both Riedel_CH30_p437-p456.indd 438 05/04/19 4:48 PM  CHAPTER 30 Pathogenesis and Control of Viral Diseases    439 TABLE 30-2 Common Routes of Viral Infection in Humans Produce Generalized Infection Plus Route of Entry Virus Group Produce Local Symptoms at Portal of Entry Specific Organ Disease Respiratory tract Parvovirus B19 Adenovirus Most types Herpesvirus Epstein-Barr virus, herpes simplex virus Varicella-zoster virus Poxvirus Smallpox virus Picornavirus Rhinoviruses Some enteroviruses Togavirus Rubella virus Coronavirus Most types Orthomyxovirus Influenza virus Paramyxovirus Parainfluenza viruses, respiratory syncytial virus Mumps virus, measles virus Mouth, intestinal tract Adenovirus Types 40 and 41 Calicivirus Noroviruses Herpesvirus Epstein-Barr virus, herpes simplex virus Cytomegalovirus Picornavirus Some enteroviruses, including poliovirus, and hepatitis A virus Reovirus Rotaviruses Skin Mild trauma Papillomavirus Most types Herpesvirus Herpes simplex virus Poxvirus Molluscum contagiosum virus, orf virus Injection Hepadnavirus Hepatitis B Herpesvirus Epstein-Barr virus, cytomegalovirus Retrovirus Human immunodeficiency virus Bites Togavirus Many species, including eastern equine encephalitis virus Flavivirus Many species, including yellow fever virus Rhabdovirus Rabies virus innate and adaptive immune responses. Interferon (IFN) and between viral and host immune factors, and the virus may other cytokines, humoral and cell-mediated immunity, and pos- enter a life-long latent state, or subsequently reactivate and sibly other host defense factors are involved. The relative impor- cause disease months to years later. tance of each component differs with the virus and the disease. The importance of host factors in influencing the out- E. Virus Shedding come of viral infections is illustrated by an incident in the The last stage in pathogenesis is the shedding of infectious 1940s in which 45,000 military personnel were inoculated virus into the environment. This is a necessary step to main- with yellow fever virus vaccine that was contaminated with tain a viral infection in populations of hosts. Shedding usu- hepatitis B virus. Although the personnel were presum- ally occurs from the body surfaces involved in viral entry (see ably subjected to comparable exposures, clinical hepatitis Figure 30-2). Shedding occurs at different stages of disease occurred in only 2% (914 cases), and of those only 4% devel- depending on the particular agent involved. During viral oped serious disease. The genetic basis of host susceptibility shedding, an infected individual is infectious to contacts. In remains to be determined for most infections. some viral infections, such as rabies, humans represent dead- In acute infections, recovery is associated with viral end infections, and shedding does not occur. Two examples clearance and viral-specific antibody production. Estab- of the pathogenesis caused by disseminated viral infections lishment of a chronic infection involves complex interplay are shown in Figure 30-3. Riedel_CH30_p437-p456.indd 439 05/04/19 4:48 PM  440   SECTION IV  Virology Influenza (respiratory) Infection Rotavirus (intestinal) Papillomavirus (skin) Body surface + Lymph node + Movement of virions Sites of shedding Blood + Possible sites of (primary viremia) replication Bone Liver + Spleen + Blood vessel + marrow + (endothelium) Blood (secondary viremia) Hepatitis B Arboviruses Nasal and oral mucous Lung +, membranes + Skin + Brain + salivary gland +, kidney + No shedding Varicella Zoster Poliovirus Measles Measles Rabies Mumps Rubella Measles (SSPE) Cytomegalovirus FIGURE 30-2 Mechanisms of spread of virus through the body in human viral infections. + indicates possible sites of viral replication; large arrows indicate sites of shedding of virus, with illustrative examples of diseases in which that route of excretion is important. Transfer from blood is by transfusion with hepatitis B and by mosquito bite in certain arboviral infections. SSPE, subacute sclerosing panencephalitis. (Modified from Mims CA, White DO: Viral Pathogenesis and Immunology. Copyright © 1984 by Blackwell Science Ltd. With permission from Wiley.) Riedel_CH30_p437-p456.indd 440 05/04/19 4:48 PM  CHAPTER 30 Pathogenesis and Control of Viral Diseases    441 TABLE 30-3 Viruses Spread Via the Bloodstream recover from primary viral infections about as well as normal people. Examples Cell Type IFN is secreted and binds to cell receptors, where it Associated DNA Viruses RNA Viruses induces an antiviral state by prompting the synthesis of other proteins that inhibit viral replication. Several pathways Lymphocytes Epstein-Barr virus, Mumps, measles, cytomegalovirus, rubella, human appear to be involved, including: (1) a dsRNA-dependent pro- hepatitis B virus, immunodeficiency tein kinase, PKR, which phosphorylates and inactivates cel- JC virus, BK virus virus lular initiation factor eIF-2 and thus prevents formation of the Monocytes- Cytomegalovirus Poliovirus, human initiation complex needed for viral protein synthesis; (2) an macrophages immunodeficiency oligonucleotide synthetase, 2-5A synthetase, which activates virus, measles virus a cellular endonuclease, RNase L, which in turn degrades Neutrophils Influenza virus mRNA; (3) a phosphodiesterase, which inhibits peptide chain Red blood cells Parvovirus B19 Colorado tick fever elongation; and (4) nitric oxide synthetase, which is induced virus by IFN-γ in macrophages. Viruses display different mechanisms that block the None (free in Togavirus, plasma) picornavirus inhibitory activities of IFNs on virus replication. Examples include specific viral proteins that block induction of expres- Modified with permission from Tyler KL, Fields BN: Pathogenesis of viral sion of IFN (herpesvirus, papillomavirus, Filovirus, hepati- infections. In Fields BN, Knipe DM, Howley PM, et al (editors). Fields Virology, 3rd ed. Lippincott-Raven, 1996. tis 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 Host Immune Response signal transduction (adenovirus, herpesviruses, hepatitis B virus), or neutralize IFN-γ by acting as a soluble IFN receptor The outcome of viral infections reflects the interplay between (myxoma virus). 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 induc- B. Adaptive Immune Response tion of cytokines such as IFNs (see later discussion). These Both humoral and cellular components of the adaptive responses help inhibit viral growth during the time it takes to immune response are involved in control of viral infections. induce specific humoral and cell-mediated immunity. Viruses elicit a tissue response different from the response to pathogenic bacteria. Whereas polymorphonuclear leukocytes A. Innate Immune Response form the principal cellular response to the acute inflamma- The innate immune response is largely mediated by IFNs, tion caused by pyogenic bacteria, infiltration with mononu- which are host-coded proteins that are members of the clear cells and lymphocytes characterizes the inflammatory large cytokine family that inhibit viral replication. They are reaction of uncomplicated viral lesions. produced very quickly (within hours) in response to viral Virus-encoded proteins serve as targets for the immune infection or other inducers and are one of the body’s first response. Virus-infected cells may be lysed by cytotoxic T responders in the defense against viral infection. IFNs also lymphocytes as a result of recognition of viral polypeptides modulate humoral and cellular immunity and have broad cell on the cell surface. Humoral immunity protects the host growth regulatory activities. against reinfection by the same virus. Neutralizing antibody There are multiple species of IFNs that fall into three gen- directed against capsid proteins blocks the initiation of viral eral groups: designated IFN-α, IFN-β, and IFN-γ (Table 30-4). infection, presumably at the stage of attachment, entry, or Both IFN-α and IFN-β are considered type I or viral IFNs; uncoating. Secretory IgA antibody is important in protecting IFN-γ is type II or immune IFN. Infection with viruses is a against infection by viruses through the respiratory or gas- potent inducer of IFN-α and IFN-β production; RNA viruses trointestinal tracts. are stronger inducers of IFN than DNA viruses. IFNs also Special characteristics of certain viruses may have pro- can be induced by double-stranded RNA and bacterial endo- found effects on the host’s immune response. Some viruses toxin. IFN-γ is not produced in response to most viruses but infect and damage cells of the immune system. The most is induced by mitogen stimulation. dramatic example is the human retrovirus HIV that infects IFNs are detectable soon after viral infection in intact T lymphocytes and destroys their ability to function, lead- animals, and viral production then decreases (Figure 30-4). ing to acquired immunodeficiency syndrome (AIDS) (see Antibody does not appear in the blood of the animal until Chapter 44). several days after viral production has abated. This tempo- Viruses have evolved a variety of ways that serve to sup- ral relationship suggests that IFN plays a primary role in the press or evade the host immune response and thus avoid being nonspecific defense of the host against viral infections, as eradicated. Often, the viral proteins involved in modulating well as the fact that agammaglobulinemic individuals usually the host response are not essential for growth of the virus in Riedel_CH30_p437-p456.indd 441 05/04/19 4:48 PM  442   SECTION IV  Virology Skin: Day Small intestine: invasion invasion 0 multiplication multiplication Regional lymph node: 1 Mesenteric lymph nodes: multiplication multiplication Bloodstream: 2 primary viremia Bloodstream: primary viremia 3 Spleen and liver: multiplication Central focus of multiplication 4 Initial antibody 5 Bloodstream: appearance secondary viremia 6 CNS: Skin: invasion focal multiplication 7 multiplication intraneural spread Antibody in serum 8 9 Early rash 10 High level of antibody Contamination in serum of environment 11 Paralysis Excretion Severe rash, 12 in feces ulceration Mousepox Human poliomyelitis FIGURE 30-3 Schematic illustrations of the pathogenesis of disseminated viral infections (mousepox and poliomyelitis). These viruses attach and replicate locally, spreading through the lymphatics and bloodstream to distant sites where they multiply further and can produce disease, followed by shedding into the environment from the initial site of infection. CNS, central nervous system. (Courtesy of F Fenner.) tissue culture, and their properties are realized only in patho- Another potential adverse effect of the immune response genesis experiments in animals. In addition to infecting cells is the development of autoantibodies through a process of the immune system and abrogating their function (HIV), known as molecular mimicry. If a viral antigen elicits anti- they may infect neurons that express little or no class I major bodies that additionally recognize an antigenic determinant histocompatibility complex (MHC) (herpesvirus), or they on a cellular protein in normal tissues, cellular injury or loss may encode immunomodulatory proteins that inhibit MHC of function unrelated to viral infection might result. The function (adenovirus, herpesvirus) or inhibit cytokine activ- host may then experience postinfectious autoimmune dis- ity (poxvirus, measles virus). Viruses may mutate and change ease, such as Guillain-Barre syndrome associated with prior antigenic sites on virion proteins (influenza virus, HIV) or measles infection. 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 Viral Persistence: Chronic and Latent the host innate immune response (polyomavirus, herpesvirus). Virus Infections The immune response to one virus or vaccine may exac- Infections are acute when a virus first infects a susceptible erbate the disease caused by subsequent infection with simi- host. Viral infections are usually self-limiting, but some may lar strains. For example, dengue virus hemorrhagic fever can persist for long periods of time in the host. Long-term virus– develop in persons who already have had at least one prior host interaction may take several forms. Chronic infections infection with another dengue serotype due to the intense (also called persistent infections) are those in which replicat- host response to infection. ing virus can be continuously detected, often at low levels; Riedel_CH30_p437-p456.indd 442 05/04/19 4:48 PM  CHAPTER 30 Pathogenesis and Control of Viral Diseases    443 TABLE 30-4 Properties of Human Interferons Virus titer Type Interferon titer Property Alpha Beta Gamma Current IFN-α IFN-β IFN-γ nomenclature Antibody titer Former Leukocyte Fibroblast Immune designation interferon Type Type I Type I Type II designation Number of genes ≥20 1 1 that code for family 0 5 10 14 21 28 Principal cell Most cell Most cell Lymphocytes source types types Days after infection Inducing agent Viruses; Viruses; Mitogens FIGURE 30-4 Illustration of kinetics of interferon and antibody dsRNA dsRNA synthesis after respiratory viral infection. The temporal relationships Stability at pH Stable Stable Labile suggest that interferons are involved in the host’s early defense 2.0 system against viral infections. Glycosylated No Yes Yes Introns in genes No No Yes Herpesviruses typically produce latent infections. HSVs Chromosomal 9 9 12 enter the sensory ganglia and persist in a noninfectious state location of (Figure 30-5). There may be periodic reactivations during genes which lesions containing infectious virus appear at peripheral Size of secreted 165 166 143 sites (eg, fever blisters). Chickenpox virus (varicella-zoster) protein also becomes latent in sensory ganglia. Recurrences are rare (number of and occur years later, usually following the distribution of a amino acids) peripheral nerve (shingles). Other members of the herpesvi- IFN receptor IFNAR IFNAR IFNGR rus family also establish latent infections, including CMV and Chromosomal 21 21 6 EBV. All may be reactivated by immunosuppression. Con- location of sequently, reactivated herpesvirus infections may be a seri- IFN receptor ous complication for persons receiving immunosuppressant genes therapy. dsRNA, double-stranded RNA; IFN, interferon. 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 mild or no clinical symptoms may be evident. Latent infec- with progressive degenerative diseases of the CNS of humans tions are those in which the virus persists in an occult (hid- (see Chapter 42). Examples of different types of persistent den or cryptic) form most of the time when no new virus is viral infections are presented in Figure 30-6. produced. There can be intermittent flare-ups of clinical dis- Spongiform encephalopathies are a group of chronic, pro- ease; infectious virus can be recovered during these times. gressive, fatal infections of the CNS caused by unconventional, Viral sequences may be detectable by molecular techniques in transmissible agents called prions (see Chapter 42). Prions tissues harboring latent infections. Inapparent or subclinical are not viruses, but are proteins whose structural alterations infections are those that give no overt sign of their presence. can cause conformational changes in host proteins leading to Chronic infections occur with a number of animal aggregation and dysfunction, and are transmissible similar to viruses, and the persistence in certain instances depends on other infectious agents. Some examples of prion infections are the age of the host when infected. In humans, for example, scrapie in sheep, bovine spongiform encephalopathy in cattle, rubella virus and CMV infections acquired in utero charac- and kuru and Creutzfeldt-Jakob disease in humans. teristically result in viral persistence that is of limited dura- tion, probably because of development of the immunologic capacity to react to the infection as the infant matures. Infants Overview of Acute Viral infected with hepatitis B virus frequently become persistently Respiratory Infections infected (chronic carriers); most carriers are asymptomatic Many types of viruses gain access to the human body via (see Chapter 35). the respiratory tract, primarily in the form of aerosolized Riedel_CH30_p437-p456.indd 443 05/04/19 4:48 PM  444   SECTION IV  Virology Herpes simplex 1 virus Varicella virus Neuron in dorsal Latent virus root ganglion Spinal cord Primary Viral transit up infection peripheral nerve Mild pharyngitis or stomatitis Chickenpox Fever Age Activation of Sunlight to face X-irradiation virus in neuron Menstruation (act via depressed CMI) Nerve section at ∗ Spinal cord ∗ Viral transit down peripheral nerve Recurrence Cold sore Zoster (shingles) FIGURE 30-5 Latent infections by herpesviruses. Examples are shown for both herpes simplex and varicella-zoster viruses. Primary infections occur in childhood or adolescence, followed by establishment of latent virus in the cerebral or spinal ganglia. Later activation causes recurrent herpes simplex or zoster. CMI, cell-mediated immunity. (Modified from Mims CA, White DO: Viral Pathogenesis and Immunology. Copyright © 1984 by Blackwell Science Ltd. With permission from Wiley.) droplets or saliva. This is the most frequent means of viral Overview of Viral Infections of the entry into the host. Successful infection occurs despite nor- Gastrointestinal Tract mal host protective mechanisms, including the mucus cov- ering most surfaces, ciliary action, collections of lymphoid Many viruses initiate infection via the alimentary tract. cells, alveolar macrophages, and secretory IgA. Many infec- Viruses are exposed in the intestinal tract to secretory IgA tions remain localized in the respiratory tract, although some and harsh elements involved in the digestion of food: acid, viruses produce their characteristic disease symptoms after bile salts (detergents), and proteolytic enzymes. Conse- systemic spread (eg, chickenpox, measles, and rubella; see quently, viruses able to initiate infection by this route are Table 30-2 and Figure 30-2). resistant to acid and bile salts. Respiratory infections impose a heavy disease burden Acute gastroenteritis is the designation for short-term worldwide. Respiratory infections are the most common gastrointestinal disease with symptoms ranging from mild, cause of mortality for children younger than 5 years, with watery diarrhea to severe febrile illness characterized by diarrheal disease the second leading cause. Disease symptoms vomiting, diarrhea, and systemic manifestations. Rotavi- exhibited by the host depend on whether the infection is con- ruses, noroviruses, and caliciviruses are major causes of gas- centrated in the upper or lower respiratory tract (Table 30-5). troenteritis. Infants and children are affected most often, and The severity of respiratory infection can range from inappar- large outbreaks can occur, making these a significant public ent to overwhelming. Although definitive diagnosis requires health concern. isolation of the virus, identification of viral gene sequences, Enteroviruses, coronaviruses, and adenoviruses also or demonstration of a rise in antibody titer, the specific viral infect the gastrointestinal tract, but those infections are typi- disease can frequently be deduced by considering the major cally asymptomatic. Some enteroviruses, notably poliovi- symptoms, the patient’s age, the time of year, and any pattern ruses, and hepatitis A virus are important causes of systemic of illness in the community. disease but do not produce intestinal symptoms. Riedel_CH30_p437-p456.indd 444 05/04/19 4:48 PM  CHAPTER 30 Pathogenesis and Control of Viral Diseases    445 = Threshold of apparent infection 1. Measles 2. Subacute sclerosing 3. Influenza, (clinical disease) panencephalitis yellow fever = Activation of virus production in the original host = Course of disease ? ? = Presence of occult virus 4. Hepatitis B 5. EEE in birds 6. Human 7. Adenoviruses 8. Herpes simplex papilloma 9. Scrapie 10. Swine flu from 11. LCM virus in 12. LCM virus in adult 13. lungworm newborn mice mice ? FIGURE 30-6 Different types of virus–host interactions: apparent (clinical disease), inapparent (subclinical), chronic, latent, occult, and slow infections. (1) Measles runs an acute, almost always clinically apparent course resulting in long-lasting immunity. (2) Measles may also be associated with persistence of latent infection in subacute sclerosing panencephalitis (see Chapter 40). (3) Yellow fever and influenza follow a pattern similar to that of measles except that infection may be more often subclinical than clinical. (4) In hepatitis B, recovery from clinical disease may be associated with chronic infection in which fully active virus persists in the blood. (5) Some infections are, in a particular species, always subclinical, such as eastern equine encephalomyelitis (EEE) in some species of birds that then act as reservoirs of the virus. (6) For human papillomavirus, the course of infection is chronic; when cervical cancer develops, the virus present is occult (not replicating). (7) Infection of humans with certain adenoviruses may be clinical or subclinical. There may be a long latent infection during which virus is present in small quantity; virus may also persist after the illness. (8) The periodic reactivation of latent HSV, which may recur throughout life in humans, often follows an initial acute episode of stomatitis in childhood. (9) Infection may be unrecognized for long periods of time before it becomes apparent. Examples of such “slow” infections characterized by long incubation periods are scrapie in sheep and kuru in humans (caused by prions, not viruses). (10) In pigs that have eaten virus-bearing lungworms, swine “flu” is occult until the appropriate stimulus induces viral production and, in turn, clinical disease. (11) Lymphocytic choriomeningitis (LCM) virus may be established in mice by in utero infection. A form of immunologic tolerance develops in which virus-specific T cells are not activated. Antibody is produced against viral proteins; this antibody and circulating LCM virus form antigen–antibody complexes that produce immune complex disease in the host. The presence of LCM virus in this chronic infection (circulating virus with little or no apparent disease) may be revealed by transmission to an indicator host (eg, adult mice from a virus-free stock). (12) All adult mice develop classic acute symptoms of LCM and frequently die. (13) The possibility is shown of infection with an occult virus that is not detectably replicating. Proof of the presence of such a virus remains a difficult task that, however, is attracting the attention of cancer investigators (see Chapter 43). TABLE 30-5 Viral Infections of the Respiratory Tract Most Common Viral Causesa Syndromes Main Symptoms Infants Children Adults Common cold Nasal obstruction, nasal Rhino Rhino Rhino discharge Adeno Adeno Corona Pharyngitis Sore throat Adeno Adeno Adeno Coxsackie Coxsackie Laryngitis or croup Hoarseness, “barking” Parainfluenza Parainfluenza Parainfluenza cough Influenza Influenza Influenza Tracheobronchitis Cough Parainfluenza Parainfluenza Influenza Respiratory syncytial Influenza Adeno Bronchiolitis Cough, dyspnea Respiratory syncytial Rare Rare Parainfluenza Pneumonia Cough, chest pain Respiratory syncytial Influenza Influenza Influenza Parainfluenza Adeno a Most commonly reported respiratory viruses vary, depending on the study design, subject population, detection methods, and other factors (eg, time of year). Riedel_CH30_p437-p456.indd 445 05/04/19 4:48 PM  446   SECTION IV  Virology Overview of Viral Skin Infections or lymphocytes. After the blood–brain barrier is breached, more extensive spread throughout the brain and spinal cord The keratinized epithelium of the skin is a tough barrier to is possible. There tends to be a correlation between the level the entry of viruses. However, a few viruses are able to breach of viremia achieved by a bloodborne neurotropic virus and its this barrier and initiate infection of the host (see Table 30-2). neuroinvasiveness. Some obtain entry through small abrasions of the skin (pox- The other pathway to the CNS is via peripheral nerves. viruses, papillomaviruses, HSVs), others are introduced by Virions can be taken up at sensory nerve or motor endings the bite of arthropod vectors (arboviruses) or infected verte- and be moved within axons, through endoneural spaces, or brate hosts (rabies virus, herpes B virus), and still others are by Schwann cell infections. Herpesviruses travel in axons to injected during blood transfusions or other manipulations be delivered to dorsal root ganglia neurons. involving contaminated needles, such as acupuncture and The routes of spread are not mutually exclusive, and a tattooing (hepatitis B virus, HIV). virus may use more than one method. Many viruses, includ- A few agents remain localized and produce lesions at the ing herpes-, toga-, flavi-, entero-, rhabdo-, paramyxo-, and site of entry (eg, papillomaviruses, molluscum contagiosum), bunyaviruses, can infect the CNS and cause meningitis, but most spread to other sites. The epidermal layer is devoid encephalitis, or both. Encephalitis caused by HSV is the most of blood vessels and nerve fibers, so viruses that infect epider- common viral cause of sporadic encephalitis in humans. mal cells tend to stay localized. Viruses that are introduced Pathologic reactions to cytocidal viral infections of the deeper into the dermis have access to blood vessels, lymphat- CNS include necrosis, inflammation, and phagocytosis by ics, dendritic cells, and macrophages and usually spread and glial cells. The cause of symptoms in some other CNS infec- cause systemic infections. tions, such as rabies, is unclear. The postinfectious enceph- Many of the generalized skin rashes associated with viral alitis that occurs after measles infections (about one per infections develop because virus spreads to the skin via the 1000 cases) and more rarely after rubella infections is char- bloodstream after replication at some other site. Such infec- acterized by autoimmune demyelination without neuronal tions originate by another route (eg, measles virus infections degeneration. occur via the respiratory tract), with hematogenous spread- There are several rare neurodegenerative disorders, ing to the skin and rash formation. sometimes referred to as slow virus infections, that are Lesions in viral skin rashes are designated as macules, uniformly fatal. Features of these infections include a long papules, vesicles, or pustules. Macules, which are caused by incubation period (months to years) followed by the onset local dilation of dermal blood vessels, progress to papules if of clinical illness and progressive deterioration, resulting in edema and cellular infiltration are present in the area. Ves- death in weeks to months; usually only the CNS is involved. icles occur if the epidermis becomes focally detached, and Some of these infections, such as progressive multifocal leu- they become pustules if an inflammatory reaction delivers koencephalopathy (JC polyomavirus) in immunocompro- polymorphonuclear leukocytes to the lesion. Ulceration and mised hosts and subacute sclerosing panencephalitis (measles scabbing follow. Hemorrhagic and petechial rashes occur virus), are caused by typical viruses. In contrast, the subacute when there is disruption of the dermal vessels. spongiform encephalopathies, typified by scrapie, are prion Skin lesions frequently play no role in viral transmission. diseases. In those infections, characteristic neuropathologic Infectious virus is not shed from the maculopapular rash of changes occur, but no inflammatory or immune response is measles or from rashes associated with arbovirus infections. elicited. In contrast, skin lesions are important in the spread of pox- viruses and HSVs. Infectious virus particles are present in high titers in the fluid of these vesiculopustular rashes, and Overview of Congenital Viral Infections they are able to initiate infection by direct contact with other Few viruses produce disease in the human fetus. Most mater- hosts. However, even in these instances, it is believed that nal viral infections do not result in viremia and fetal involve- virions in oropharyngeal secretions may be more important ment. However, if the virus crosses the placenta and infection to disease transmission than the skin lesions. occurs in utero, serious damage may be done to the fetus. Three principles are involved in the production of con- genital defects: (1) the ability of the virus to infect the preg- Overview of Viral Infections of the nant woman and be transmitted to the fetus; (2) the stage of Central Nervous System gestation at which infection occurs; and (3) the ability of the Viruses can gain access to the brain by two routes: by the virus to cause damage to the fetus directly (by infection of bloodstream (hematogenous spread) and by peripheral nerve the fetus) or indirectly (by infection of the mother), resulting fibers (neuronal spread). Access from the blood may occur in an altered fetal environment (eg, fever). The sequence of by growth through the endothelium of small cerebral ves- events that may occur before and after viral invasion of the sels; by passive transport across the vascular endothelium; fetus is shown in Figure 30-7. by passage through the choroid plexus to the cerebrospinal Rubella virus and CMV are presently the primary viruses fluid; or by transport within infected monocytes, leukocytes, responsible for congenital defects in humans (see Chapters 33 Riedel_CH30_p437-p456.indd 446 05/04/19 4:48 PM  CHAPTER 30 Pathogenesis and Control of Viral Diseases    447 Virus may destroy rapidly replicating fetal cells or alter cell func- tion. Lytic viruses, such as herpes simplex, may result in fetal death. Less cytolytic viruses, such as rubella, may slow the Susceptible rate of cell division. If this occurs during a critical phase in pregnant woman organ development, structural defects and congenital anom- Spontaneous Normal alies may result. abortion Maternal fetus Many of the same viruses can produce serious disease in Vir gin a infection em newborns (see Table 30-6). Such infections may be contracted va ia a from the mother during delivery (perinatal) from contami- Vi nated genital secretions, stool, or blood. Less commonly, infections may be acquired during the first few weeks after Amnionic Placental infection Ova infection 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. Fetal infection Effect of Host Age Host age is a factor in viral pathogenicity. More severe dis- ease is often produced in newborns. In addition to matu- ration of the immune response with age, there seem to be Normal Infected Fetal death Malformation age-related changes in the susceptibility of certain cell types fetus fetus (abortion; ( ± death) to viral infection. Viral infections usually can occur in all age ( ± disease) stillbirth) groups but may have their major impact at different times of life. Examples include rubella, which is most serious during FIGURE 30-7 Viral infection of the fetus. (Courtesy of L Catalano gestation; rotavirus, which is most serious for infants; and and J Sever.) St. Louis encephalitis, which is most serious in elderly adults. and 40). Congenital infections can also occur with herpes Diagnosis of Viral Infections simplex, varicella-zoster, hepatitis B, measles, and mumps There are several different ways in which viral infections virus, as well as with HIV, parvovirus, and some enterovi- are diagnosed (Figure 30-8) (see Chapter 47). Rapid antigen ruses (Table 30-6). detection methods use virus-specific monoclonal antibod- In utero infections may result in fetal death, premature ies for detection. Nucleic acid or polymerase chain reaction birth, intrauterine growth retardation, or persistent postnatal (PCR) tests use specific primers and probes to detect viral infection. Developmental malformations, including congeni- nucleic acid. The PCR tests can be multiplexed, allowing tal heart defects, cataracts, deafness, microcephaly, and limb detection of multiple viruses concurrently. Virus culture hypoplasia, may result. Viral infection and multiplication and serological testing for specific antibody responses are TABLE 30-6 Acquisition of Significant Perinatal Viral Infections Severity by Time of Infection Prenatal Natal (During Postnatal Neonatal Incidence Virus (In Utero) Delivery) (After Delivery) (per 1000 Live Births) Rubella + − Rare 0.1–0.7 Cytomegalovirus + ++ + 5–25 Herpes simplex + ++ + 0.03–0.5 Varicella-zoster + Rare Rare Rare Hepatitis B + ++ + 0–7 Enterovirus + ++ + Uncommon Human immunodeficiency + ++ + Variable virus Parvovirus B19 + − Rare Rare Riedel_CH30_p437-p456.indd 447 05/04/19 4:48 PM  448   SECTION IV  Virology (1) Cells infected with (2) Cells infected with herpes simplex virus influenza virus Signs and symptoms: Patient is observed for manifestations of typical virus infections. This is herpes simplex, type 1. Cells taken from patient are examined for evidence of viral infection, such as cytopathic effects (1) or virus antigen detected by fluorescent staining (2). Rotavirus Hepatitis B Embryo Cell culture Dane Filament particle Culture techniques: Viruses require a living host to multiply. Electron microscope is used to view virus directly. Viruses are sufficiently unique in structure that they can be differentiated to family or genus. Probes Positive reaction Western blot for HIV Genetic analysis (PCR): Detection of viral nucleic acid Serological testing for antibodies using specific probes. FIGURE 30-8 Summary of methods used to diagnose viral infections. Antigen detection tests and nucleic acid assays are most commonly used diagnostically because results can be obtained quickly. (Reproduced with permission from Talaro KP: Foundations in Microbiology: Basic Principles, 6th ed. McGraw-Hill, 2008. © McGraw-Hill Education.) Riedel_CH30_p437-p456.indd 448 05/04/19 4:48 PM  CHAPTER 30 Pathogenesis and Control of Viral Diseases    449 slow to provide results but are useful for epidemiologic and into the structure of other viral targets, and to develop anti- research studies. More recently developed nucleic acid- virals for viruses for which no drugs currently exist. based technology such as automated multiplexed PCR, high-density microarrays, and deep sequencing allow for A. Nucleoside and Nucleotide Analogs detection of multiple viruses in a single assay. Because there The majority of available antiviral agents are nucleoside are relatively few targeted antiviral therapies, knowledge of analogs. They inhibit nucleic acid replication by inhibition the specific infecting viral agent may not alter patient treat- of viral polymerases essential for nucleic acid replication. In ment, but it can be useful to determine the prognosis and for addition, some analogs are incorporated into the nucleic acid patient management. 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 PREVENTION AND TREATMENT OF are able to specifically inhibit virus-encoded enzymes, with minimal inhibition of analogous host cell enzymes. Because VIRAL INFECTIONS of high mutation rates, virus variants resistant to the drug Antiviral Chemotherapy usually arise over time, sometimes quite rapidly. The use of combinations of antiviral drugs can delay the emergence of Unlike viruses, bacteria and protozoans do not rely on host resistant variants (eg, “triple-drug” therapy used to treat HIV cellular machinery for replication, so processes specific to infections). these organisms provide ideal targets for the development of antibacterial and antiprotozoal drugs. Because viruses are B. Reverse Transcriptase Inhibitors obligate intracellular parasites, antiviral agents must be capa- ble of selectively inhibiting viral functions without damaging Nonnucleoside reverse transcriptase inhibitors act by bind- the host, making the development of such drugs very difficult. ing directly to virally encoded reverse transcriptase and Another limitation is that many rounds of virus replication inhibiting its activity. However, resistant mutants emerge occur during the incubation period and the virus has spread rapidly, making these useful only in the context of multi- before symptoms appear, making drug treatment after the drug therapy. development of clinical symptoms relatively ineffective. There is a need for antiviral drugs active against viruses C. Protease Inhibitors for which vaccines are not available or not highly effective Protease inhibitors were first designed by computer model- because of a multiplicity of serotypes (eg, rhinoviruses) or ing as peptidomimetic agents that fit into the active site of because of constantly changing viral antigens (eg, influenza, the HIV protease enzyme. Such drugs inhibit the viral pro- HIV). Antivirals can be used to treat established infections tease that is required at the late stage of the replicative cycle when vaccines would not be effective. Antivirals are needed to cleave the viral gag and gag-pol polypeptide precursors to to reduce morbidity and economic loss caused by viral infec- form the mature virion core and activate the reverse tran- tions and to treat increasing numbers of immunosuppressed scriptase that will be used in the next round of infection. Pro- patients who are at increased risk of severe disease. tease inhibitors have been used successfully for treatment of Molecular virology studies are succeeding in identifying HIV and HCV infections. virus-specific functions that can serve as targets for antiviral therapy. Stages during viral infections that could be targeted D. Integrase Inhibitors include attachment of virus to host cells, uncoating of the viral HIV integrase inhibitors block the activity of viral integrase, genome, viral nucleic acid synthesis, translation of viral pro- a key enzyme in HIV replication. Without integration of teins, and assembly and release of progeny virus particles. It virally encoded DNA into the host chromosome, the life cycle has been very difficult to develop antivirals that can distin- cannot continue. Raltegravir was the first integrase inhibitor guish viral from host replicative processes, but there have been to be approved in 2007. successful drugs developed, particularly for chronic infec- tions (eg, HIV, hepatitis C). A number of compounds have E. Fusion Inhibitors been developed that are of value in treatment of viral diseases (Table 30-7). The mechanisms of action vary among antivi- HIV fusion inhibitors act by disrupting the fusion of viral rals, and can target a viral protein enzymatic activity or block envelope with the cell membrane, preventing cellular infec- host–virus protein interaction. Some drugs must be activated tion. The prototype agent, enfuvirtide, is a peptide that binds by enzymes in the cell before it can act as an inhibitor of viral to gp41 and blocks the required conformational change that replication; the most selective drugs are activated by a virus- initiates membrane fusion. encoded enzyme in the infected cell. Future work is necessary to minimize the emergence of F. Other Types of Antiviral Agents drug-resistant variant viruses, to reduce drug toxicities, to A number of other types of compounds have been shown to design more specific antivirals based on molecular insights possess some antiviral activity under certain conditions. Riedel_CH30_p437-p456.indd 449 05/04/19 4:48 PM  450   SECTION IV  Virology TABLE 30-7 Examples of Antiviral Compounds Used for Treatment of Viral Infections Drug Nucleoside Analog Mechanism of Action Viral Spectrum Acyclovir Yes Viral polymerase inhibitor Herpes simplex, varicella-zoster Adefovir Yes Viral polymerase inhibitor HBV Amantadine No Blocks viral uncoating Influenza A Boceprevir No HCV protease inhibitor HCV Cidofovir No Viral polymerase inhibitor Cytomegalovirus, herpes simplex, polyomavirus Didanosine (ddI) Yes Reverse transcriptase inhibitor HIV-1, HIV-2 Entecavir Yes Reverse transcriptase inhibitor HBV Foscarnet No Viral polymerase inhibitor Herpesviruses, HIV-1, HBV Enfuvirtide No HIV fusion inhibitor (blocks viral entry) HIV-1 Ganciclovir Yes Viral polymerase inhibitor Cytomegalovirus Indinavir No HIV protease inhibitor HIV-1, HIV-2 Interferon (pegylated No Immune response activator HCV, HBV, others interferon) Lamivudine (3TC) Yes Reverse transcriptase inhibitor HIV-1, HIV-2, HBV Lopinavir No HIV protease inhibitor HIV-1 Maraviroc No Entry inhibitor (blocks binding to CCR5) HIV-1 Nevirapine No Reverse transcriptase inhibitor HIV-1 Oseltamivir No Viral neuraminidase inhibitor Influenza A and B Raltegravir No Integrase inhibitor HIV-1 Ribavirin Yes Perhaps blocks capping of viral mRNA Respiratory syncytial virus, influenza A and B, Lassa fever, HCV, others Ritonavir No HIV protease inhibitor HIV-1, HIV-2 Saquinavir No HIV protease inhibitor HIV-1, HIV-2 Simeprevir No HCV protease inhibitor HCV Sofosbuvir Yes Viral polymerase inhibitor HCV Stavudine (d4T) Yes Reverse transcriptase inhibitor HIV-1, HIV-2 Telaprevir No HCV protease inhibitor HCV Telbivudine Yes Viral polymerase inhibitor HBV Tenofovir Yes Viral polymerase inhibitor HBV Trifluridine Yes Viral polymerase inhibitor Herpes simplex, cytomegalovirus, vaccinia Valacyclovir Yes Viral polymerase inhibitor Herpesviruses Vidarabine Yes Viral polymerase inhibitor Herpesviruses, vaccinia, HBV Zalcitabine (ddC) Yes Reverse transcriptase inhibitor HIV-1, HIV-2, HBV Zidovudine (AZT) Yes Reverse transcriptase inhibitor HIV-1, HIV-2, HTLV-1 HBV, hepatitis B virus; HCV, hepatitis C virus; HIV-1, HIV-2, human immunodeficiency virus types 1 and 2; HTLV-1, human T-cell leukemia virus type 1; mRNA, messenger RNA. Riedel_CH30_p437-p456.indd 450 05/04/19 4:48 PM  CHAPTER 30 Pathogenesis and Control of Viral Diseases    451 Amantadine and rimantadine specifically inhibit influ- A. General Principles enza A viruses by blocking viral uncoating. They must be Immunity to viral infection is based on the development of administered very early in infection to have a significant an immune response to specific antigens located on the sur- effect. face of virus particles or virus-infected cells. For enveloped Oseltamivir is a neuraminidase inhibitor that prevents viruses, the important antigens are the surface glycoproteins. the release of influenza virus particles from infected cells. Although infected animals may develop antibodies against Foscarnet (phosphonoformic acid) is an organic analog virion core proteins or nonstructural proteins involved in viral of inorganic pyrophosphate. It selectively inhibits viral DNA replication, that immune response is believed to play little or polymerases and reverse transcriptases at the pyrophosphate- no role in the development of resistance to infection. binding site. Vaccines are available for the prevention of several Acyclovir is a guanosine analog DNA polymerase significant human diseases. Currently available vaccines inhibitor used for the treatment of HSV and varicella-zoster (Table 30-8) are described in detail in the chapters dealing virus infections. The prodrug valacyclovir is an esteri- with specific virus families and diseases. fied version that can be taken orally and is metabolized to The pathogenesis of a particular viral infection influ- acyclovir. ences the objectives of immunoprophylaxis. Mucosal immu- Ganciclovir is a nucleoside DNA polymerase inhibi- nity (local IgA) is important in resistance to infection by tor active against CMV whose specificity comes from viruses that replicate in mucosal membranes (rhinoviruses, phosphorylation by virus-specific kinases only in virally influenza viruses, rotaviruses) or invade through the mucosa infected cells. Valganciclovir is the orally available prodrug (papillomavirus). Viruses that have a viremic mode