Jawetz Chapter 33.pdf

33 C H A P T E R Herpesviruses...

33 C H A P T E R Herpesviruses The herpesvirus family contains several important human The enveloped form measures 150–200 nm; the “naked” viral pathogens. Clinically, the herpesviruses exhibit a wide virion, 125 nm. spectrum of diseases. Some have an extensive host-cell range, The double-stranded DNA genome (125–240 kbp) is lin- and others have a narrow host-cell range. The outstand- ear. A striking feature of herpesvirus DNAs is their sequence ing property of herpesviruses is their ability to establish arrangement (Figure 33-1). Herpesvirus genomes possess lifelong persistent infections in their hosts and to undergo terminal and internal repeated sequences. Some members periodic reactivation. Their frequent reactivation in elderly can undergo genome rearrangements, giving rise to differ- and immunosuppressed patients causes serious health com- ent genome “isomers.” The base composition of herpesvirus plications. Curiously, the reactivated infection may be clini- DNAs varies from 31% to 75% (G + C). There is little DNA cally quite different from the disease caused by the primary homology among different herpesviruses except for HSV-1 infection. Herpesviruses possess a large number of genes, and HSV-2, which show 50% sequence homology, and human some of which have proved to be susceptible to antiviral herpesviruses 6 and 7 (HHV-6 and HHV-7), which dis- chemotherapy. play limited (30–50%) sequence homology. Treatment with The herpesviruses that commonly infect humans are restriction endonucleases yields characteristically different numbered from human herpesvirus 1 (HHV-1) to HHV-8 but cleavage patterns for herpesviruses and even for different are commonly referred to by their individual virus names. In strains of each type. This “fingerprinting” of strains allows order, these are herpes simplex virus types 1 and 2 (HSV-1, epidemiologic tracing of a given strain. HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus The herpesvirus genome is large and encodes at least (EBV), cytomegalovirus (CMV), herpesvirus 6 (HHV-6), 100 different proteins. Of these, more than 35 polypeptides herpesvirus 7 (HHV-7), and herpesvirus 8 (HHV-8, also are involved in the structure of the virus particle; at least 10 known as Kaposi sarcoma-associated herpesvirus [KSHV]). are part of the viral envelope. Herpesviruses encode an array Herpes B virus of monkeys can also infect humans. There are of virus-specific enzymes involved in nucleic acid metabo- nearly 100 viruses of the herpes group that infect many dif- lism, DNA synthesis, gene expression, and protein regulation ferent animal species. (DNA polymerase, helicase-primase, thymidine kinase, tran- scription factors, protein kinases). Many herpesvirus genes appear to be viral homologs of cellular genes. PROPERTIES OF HERPESVIRUSES Important properties of herpesviruses are summarized in Classification Table 33-1. Taxonomic classification of the numerous members of the herpesvirus family is complicated. A useful division into subfamilies is based on biologic properties of the agents Structure and Composition (Table 33-2). Alphaherpesviruses are fast-growing, cytolytic Herpesviruses are large viruses. Different members of the viruses that tend to establish latent infections in neurons; group share architectural details and are indistinguishable HSV (genus Simplexvirus) and VZVs (genus Varicellovirus) by electron microscopy. All herpesviruses have a core of are members. Betaherpesviruses are slow growing and may double-stranded DNA, in the form of a toroid, surrounded be cytomegalic (massive enlargements of infected cells) and by a protein coat that exhibits icosahedral symmetry and become latent in secretory glands and kidneys; CMV is clas- has 162 capsomeres. The nucleocapsid is surrounded by an sified in the Cytomegalovirus genus. Also included here, in envelope that is derived from the nuclear membrane of the the genus Roseolovirus, are HHV-6 and HHV-7; by biologic infected cell and contains viral glycoprotein spikes about criteria, they are similar to gammaherpesviruses because 8 nm long. An amorphous, sometimes asymmetric structure they infect lymphocytes (T lymphotropic), but molecular between the capsid and envelope is designated the tegument. analyses of their genomes reveal that they are more closely 473 Riedel_CH33_p473-p498.indd 473 04/04/19 5:02 PM  474   SECTION IV  Virology TABLE 33-1 Important Properties of Herpesviruses Class Sequence arrangement Isomers LTR RTR Virion: Spherical, 150–200 nm in diameter (icosahedral) A 1 Genome: Double-stranded DNA, linear, 125–240 kbp, reiterated B 1 sequences R4 R3 R2 R1 Proteins: More than 35 proteins in virion C 1 U1 IR US TR Envelope: Contains viral glycoproteins, Fc receptors D 2 Replication: Nucleus, bud from nuclear membrane an b U1 b′ a′nc′ US ca E 4 Outstanding characteristics: F 1 Encode many enzymes FIGURE 33-1 Schematic diagram of sequence arrangements Establish latent infections of herpesvirus DNAs. Genome classes A, B, C, D, E, and F are Persist indefinitely in infected hosts exemplified by channel catfish virus, herpesvirus saimiri, Epstein- Barr virus, varicella-zoster virus, herpes simplex viruses, and tupaia Frequently reactivated in immunosuppressed hosts herpesvirus, respectively. Horizontal lines represent unique regions. Some cause cancer Reiterated domains are shown as rectangles: left and right terminal repeats (LTR and RTR) for class A; repeats R1–R4 for internal repeats of class C; and internal and terminal repeats (IR and TR) of class D. In class B, terminal sequences are reiterated numerous times at both termini. The termini of class E consist of two elements. The terminal related to the betaherpesviruses. Gammaherpesviruses, sequences (ab and ca) are inserted in an inverted orientation exemplified by EBV (genus Lymphocryptovirus), infect and separating the unique sequences into long (Ul) and short (Us) become latent in lymphoid cells. HHV-8/KSHV is classified domains. Genomes of class F have no terminal reiterations. The in the Rhadinovirus genus. components of the genomes in classes D and E invert. In class D Many herpesviruses infect animals, the most notable (varicella-zoster virus), the short component inverts relative to the being herpes B virus (herpesvirus simiae or cercopithecine long, and the DNA forms two populations (isomers) differing in herpesvirus 1) in the Simplexvirus genus; herpesviruses sai- the orientation of the short component. In class E (herpes simplex miri and ateles of monkeys, both in genus Rhadinovirus; virus), both the short and long components can invert, and viral marmoset herpesvirus (genus Simplexvirus); and pseudora- DNA consists of four isomers. (Reproduced with permission from bies virus of pigs and infectious bovine rhinotracheitis virus Roizman B: Herpesviridae: A brief introduction. In Fields BN, of cattle, both in genus Varicellovirus. Knipe DM [editors-in-chief]. Virology, 2nd ed. Raven Press, 1990, pp. 1787–1793.) There is little antigenic relatedness among members of the herpesvirus group. Only HSV-1 and HSV-2 share a sig- nificant number of common antigens. HHV-6 and HHV-7 exhibit a few cross-reacting epitopes. late transcripts are produced that give rise to “γ” proteins. More than 50 different proteins are synthesized in herpes- virus-infected cells. Many α and β proteins are enzymes or Herpesvirus Replication DNA-binding proteins; most of the γ proteins are struc- The replication cycle of HSV is summarized in Figure 33-2. tural components. The virus enters the cell by fusion with the cell membrane Viral DNA is transcribed throughout the replicative after binding to specific cellular receptors via envelope cycle by cellular RNA polymerase II but with the participa- glycoproteins. Several herpesviruses bind to cell surface tion of viral factors. Viral DNA is synthesized by a rolling- glycosaminoglycans, principally heparan sulfate. Virus circle mechanism. Herpesviruses differ from other nuclear attachment also involves binding to one of several core- DNA viruses in that they encode a large number of enzymes ceptors (eg, members of the immunoglobulin superfam- involved in DNA synthesis. These enzymes have been good ily). After fusion, the capsid is transported through the targets for development of antiviral drugs. Newly synthesized cytoplasm to a nuclear pore, uncoating occurs, and the viral DNA is packaged into preformed empty nucleocapsids in DNA becomes associated with the nucleus. The viral DNA the cell nucleus. forms a circle immediately upon release from the capsid. Maturation occurs by budding of nucleocapsids through Expression of the viral genome is tightly regulated and the altered inner nuclear membrane. Enveloped virus sequentially ordered in a cascade fashion. VP16, a tegu- particles are then transported by vesicular movement to the ment protein, complexes with several cellular proteins and surface of the cell. activates initial viral gene expression. Immediate-early The length of the replication cycle varies from about genes are expressed, yielding “α” proteins. These proteins 18 hours for HSV to more than 70 hours for CMV. Cells pro- permit expression of the early set of genes, which are trans- ductively infected with herpesviruses are invariably killed. lated into “β” proteins. Viral DNA replication begins, and Host macromolecular synthesis is shut off early in infection; Riedel_CH33_p473-p498.indd 474 04/04/19 5:02 PM  CHAPTER 33 Herpesviruses   475 TABLE 33-2 Classification of Human Herpesviruses Biologic Properties Examples Official Name Subfamily Growth Cycle and Latent Genus (“Human (“-herpesvirinae”) Cytopathology Infections (“-virus”) Herpesvirus”) Common Name Alpha Short, cytolytic Neurons Simplex 1 Herpes simplex virus type 1 2 Herpes simplex virus type 2 Varicello 3 Varicella-zoster virus Beta Long, cytomegalic Glands, kidneys Cytomegalo 5 Cytomegalovirus Long, lymphoproliferative Lymphoid tissue Roseolo 6 Human herpesvirus 6 7 Human herpesvirus 7 Gamma Variable, Lymphoid tissue Lymphocrypto 4 Epstein-Barr virus lymphoproliferative Rhadino 8 Kaposi sarcoma-associated herpesvirus normal cellular DNA and protein synthesis virtually stop as are infected for the first time with varicella-zoster virus can viral replication begins. Cytopathic effects induced by human develop serious viral pneumonia. herpesviruses are quite distinct and can include intranuclear CMV replicates in epithelial cells of the respiratory inclusion bodies (Figure 33-3). tract, salivary glands, and kidneys and persists in lympho- The number of potential protein-coding open-reading cytes. It causes an infectious mononucleosis (heterophile frames in herpesvirus genomes ranges from about 70 to more antibody-negative). In newborns, disseminated cytomegalic than 200. In the case of HSV, about half of the genes are not inclusion disease may occur. CMV is an important cause needed for growth in cultured cells. The other genes are of congenital defects, neonatal hearing loss, and mental probably required for viral survival in vivo in natural hosts. retardation. Herpesviruses have been found to express multiple EBV replicates in epithelial cells of the oropharynx and microRNAs, small (∼22 nucleotides) single-stranded RNAs parotid gland and establishes latent infections in lympho- that function posttranscriptionally to regulate gene expres- cytes. It causes infectious mononucleosis and can induce sion. These viral microRNAs are important in regulating cel- human lymphoproliferative disorders, especially in immu- lular functions and entry into or exit from (or both) the latent nocompromised patients. phase of the virus life cycle and provide attractive targets for HHV-6 infects T lymphocytes. It is typically acquired in novel antiviral therapy development. early infancy and causes exanthem subitum (roseola infan- tum) as well as infections in immunocompromised patients. HHV-7, also a T-lymphotropic virus, has not yet been defini- Overview of Herpesvirus Diseases tively linked to any specific disease. HHV-8 is associated with A wide variety of diseases are associated with infection by the development of Kaposi sarcoma, a vascular tumor that is herpesviruses. Primary infection and reactivated disease by common in patients with AIDS. a given virus may involve different cell types and present dif- Herpes B virus of macaque monkeys can infect humans ferent clinical pictures. upon exposure to live animals or tissue samples. Such infec- HSV-1 and HSV-2 infect epithelial cells and establish tions are rare, but those that occur usually result in severe latent infections in neurons. Type 1 is classically associated neurologic disease and are frequently fatal. with oropharyngeal lesions and causes recurrent attacks of Human herpesviruses are frequently reactivated in the “fever blisters.” Type 2 primarily infects the genital mucosa elderly and immunosuppressed patients (eg, transplant recip- and is mainly responsible for genital herpes, though the ients and cancer patients) and may cause severe disease, such anatomical specificity of these viruses is diminishing. Both as pneumonia or lymphomas. viruses can also cause neurologic disease. HSV-1 is the lead- Herpesviruses have been linked with malignant diseases ing viral cause of sporadic encephalitis in the United States. in humans and lower animals: EBV with Burkitt lymphoma Both types 1 and 2 can cause neonatal infections that are of African children, with nasopharyngeal carcinoma, and often severe. with other lymphoproliferative disorders; KSHV with Kaposi VZV causes chickenpox (varicella) on primary infection sarcoma; Marek disease virus with a lymphoma of chickens; and establishes latent infection in neurons. Upon reactiva- and a number of primate herpesviruses with reticulum cell tion, the virus causes herpes zoster (shingles). Adults who sarcomas and lymphomas in monkeys. Riedel_CH33_p473-p498.indd 475 04/04/19 5:02 PM  476   SECTION IV  Virology Penetration and uncoating Adsorption Cytoplasm Nucleus 1 Immediate– α-Proteins early 2 Early β-Proteins Concatemeric DNA 3 γ-Proteins Late Nucleocapsid 4 assembly Budding Proteins Rough ER FIGURE 33-2 Replication cycle of herpes simplex virus. (1) Virus fuses with plasma membrane, and viral DNA is released from capsid at nuclear pore followed by circularization of genome and transcription of immediate-early genes. (2) α-Proteins, products of Golgi Transport vesicle immediate-early genes, stimulate transcription of early apparatus genes. (3) β-Proteins, products of early genes, function in DNA replication, yielding concatemeric DNA. Late genes are transcribed. (4) γ-Proteins, products of late genes and consisting primarily of viral structural proteins, participate in virion assembly. Unit-length viral DNA is cleaved from concatemers and packaged into capsids. Enveloped viral particles accumulate in the Exocytosis endoplasmic reticulum (ER) and are transported from the cell. (Reproduced with permission from Willey JM, Sherwood LM, Woolverton CJ: Prescott, Harley, and Klein’s Microbiology, 7th ed. McGraw-Hill, 2008. © McGraw-Hill Education.) HERPESVIRUS INFECTIONS Properties of the Viruses IN HUMANS There are two distinct HSV, types 1 and 2 (HSV-1 and HSV-2) (Table 33-3). Their genomes are similar in organi- HERPES SIMPLEX VIRUSES zation and exhibit substantial sequence homology. However, they can be distinguished by sequence analysis or by restric- HSV are extremely widespread in the human popula- tion enzyme analysis of viral DNA. The two viruses cross- tion. They exhibit a broad host range, being able to rep- react serologically, but some unique proteins exist for each licate in many types of cells and to infect many different type. Classically, HSV-1 is spread by contact, usually involv- animals. They grow rapidly and are highly cytolytic. The ing infected saliva and HSV-2 is transmitted sexually or from HSVs are responsible for a spectrum of diseases, ranging a maternal genital infection to a newborn. However, these from gingivostomatitis to keratoconjunctivitis, encephali- patterns are becoming less distinct, and both viruses can tis, genital disease, and infections of newborns. The HSVs cause either presentation. establish latent infections in nerve cells and recurrences The HSV growth cycle proceeds rapidly, requir- are common. ing 8–16 hours for completion. The HSV genome is large Riedel_CH33_p473-p498.indd 476 04/04/19 5:02 PM  CHAPTER 33 Herpesviruses   477 A B C D FIGURE 33-3 Cytopathic effects induced by herpesviruses. A: Herpes simplex virus in HEp-2 cells (hematoxylin and eosin stain, 57×), with early focus of swollen, rounded cells. B: Varicella-zoster virus in human kidney cells (hematoxylin and eosin stain, 228×), with multinucleated giant cell containing acidophilic intranuclear inclusions (arrow). C: Cytomegalovirus in human fibroblasts (unstained, 35×) with two foci of slowly developing cytopathic effect. D: Cytomegalovirus in human fibroblasts (hematoxylin and eosin stain, 228×), showing giant cells with acidophilic inclusions in the nuclei (small arrow) and cytoplasm (large arrow), the latter being characteristically large and round. (Courtesy of I Jack; reproduced from White DO, Fenner FJ: Medical Virology, 3rd ed. Academic Press, 1986.) (∼150 kbp) and can encode at least 70 polypeptides; the func- Characteristic histopathologic changes include balloon- tions of many of the proteins in replication or latency are not ing of infected cells, production of Cowdry type A intra- known. At least eight viral glycoproteins are among the viral nuclear inclusion bodies, margination of chromatin, and late gene products. One (gD) is the most potent inducer of formation of multinucleated giant cells. Cell fusion provides neutralizing antibodies. Glycoprotein C is a complement an efficient method for cell-to-cell spread of HSV, even in the (C3b)-binding protein, and gE is an Fc receptor, binding to presence of neutralizing antibody. the Fc portion of immunoglobulin G (IgG). Glycoprotein G is type specific and allows for antigenic discrimination between B. Primary Infection HSV-1 (gG-1) and HSV-2 (gG-2). HSV is transmitted by contact of a susceptible person with an individual excreting virus. The virus must encounter mucosal surfaces or broken skin for an infection to be ini- Pathogenesis and Pathology tiated (unbroken skin is resistant). Viral replication occurs A. Pathology first at the site of infection. Virus then invades local nerve Because HSV causes cytolytic infections, pathologic changes endings and is transported by retrograde axonal flow to dor- are due to necrosis of infected cells together with the inflam- sal root ganglia, where, after further replication, latency is matory response. Lesions induced in the skin and mucous established. Whereas oropharyngeal HSV infections result in membranes by HSV-1 and HSV-2 are the same and resemble latent infections in the trigeminal ganglia, genital HSV infec- those of VZV. Changes induced by HSV are similar for pri- tions lead to latently infected sacral ganglia. mary and recurrent infections but vary in degree, reflecting Primary HSV infections are usually mild; in fact, most the extent of viral cytopathology. are asymptomatic. Only rarely does systemic disease develop. Riedel_CH33_p473-p498.indd 477 04/04/19 5:02 PM  478   SECTION IV  Virology TABLE 33-3 Comparison of Herpes Simplex Virus Types 1 and 2 Characteristics HSV-1 HSV-2 Biochemical Viral DNA base composition (G + C) (%) 67 69 Buoyant density of DNA (g/cm ) 3 1.726 1.728 Buoyant density of virions (g/cm ) 3 1.271 1.267 Homology between viral DNAs (%) ∼50 ∼50 Biologic Animal vectors or reservoirs None None Typical site of latency Trigeminal ganglia Sacral ganglia Epidemiologic Age of primary infection Young children Young adults Typical transmission Contact (often saliva) Sexual Typical clinical associations Primary infection:   Gingivostomatitis + −   Pharyngotonsillitis + −   Keratoconjunctivitis + −   Neonatal infections ± + Recurrent infection:    Cold sores, fever blisters + −   Keratitis + − Primary or recurrent infection: Cutaneous herpes    Skin above the waist + ±    Skin below the waist ± +    Hands or arms + + Herpetic whitlow + + Eczema herpeticum + − Genital herpes ± + Herpes encephalitis + − Herpes meningitis ± + Modified with permission from Oxman MN: Herpes stomatitis. In Braude AI, Davis CE, Fierer J (editors). Infectious Diseases and Medical Microbiology, 2nd ed. Saunders, 1986:752. Occasionally, HSV can enter the central nervous system and host. No virus can be recovered between recurrences at or near cause meningitis or encephalitis. Widespread organ involve- the usual site of recurrent lesions. Provocative stimuli can reac- ment can result when an immunocompromised host is not tivate virus from the latent state, including axonal injury, fever, able to limit viral replication and viremia ensues. physical or emotional stress, and exposure to ultraviolet light. The virus transits via axons back to the peripheral site, and C. Latent Infection replication proceeds at the skin or mucous membranes. Spon- Virus resides in latently infected ganglia in a nonreplicating taneous reactivations occur despite HSV-specific humoral state; only a very few viral genes are expressed. Viral persis- and cellular immunity in the host. However, this immunity tence in latently infected ganglia lasts for the lifetime of the limits local viral replication so that recurrent infections are Riedel_CH33_p473-p498.indd 478 04/04/19 5:02 PM  CHAPTER 33 Herpesviruses   479 less extensive and less severe. Many recurrences are asymp- tomatic, reflected only by viral shedding in secretions. When symptomatic, episodes of recurrent HSV are most often mani- fested as cold sores (fever blisters) near the lip. More than 80% of the human population harbor HSV-1 in a latent form, but relatively few experience recurrences. It is not known why some individuals have reactivations and others do not. Clinical Findings HSV-1 and HSV-2 may cause many clinical entities, and the infections may be primary or recurrent (see Table 33-3). Primary infections occur in persons without antibodies and in most individuals are clinically inapparent but result in antibody production and establishment of latent infections in sensory ganglia. Recurrent lesions are common. A A. Oropharyngeal Disease Primary HSV-1 infections are usually asymptomatic. Symp- tomatic disease occurs most frequently in small children (1–5 years of age) and involves the buccal and gingival mucosa of the mouth (Figure 33-4A). The incubation period is short (∼3–5 days, with a range of 2–12 days), and clinical illness lasts 2–3 weeks. Symptoms include fever, sore throat, vesicular and ulcerative lesions, gingivostomatitis, and mal- aise. Gingivitis (swollen, tender gums) is the most striking and common lesion. Primary infections in adults commonly cause pharyngitis and tonsillitis. Localized lymphadenopa- thy may occur. Recurrent disease is characterized by a cluster of vesicles most commonly localized at the border of the lip (Figure 33-4B). Intense pain occurs at the outset but fades over 4–5 days. Lesions progress through the pustular and crust- B ing stages, and healing without scarring usually completes in FIGURE 33-4 A: Primary herpes simplex gingivostomatitis. 8–10 days. The lesions may recur, repeatedly and at various (Courtesy of JD Millar. Source: Centers for Disease Control intervals, in similar locations. The frequency of recurrences and Prevention, Public Health Image Library, ID# 2902, 2008.) varies widely among individuals. Many recurrences of oral B: Recurrent herpes simplex labialis. (Used with permission from shedding are asymptomatic and of short duration (24 hours). Berger TG, Dept Dermatology, UCSF. Reproduced from McPhee SJ, Papadakis MA [editors]: Current Medical Diagnosis & Treatment, B. Keratoconjunctivitis 48th ed. McGraw-Hill, 2009. © McGraw-Hill Education.) HSV infections may occur in the eye, producing severe kera- toconjunctivitis. Recurrent lesions of the eye are common lesions are very painful and may be associated with fever, and appear as dendritic keratitis or corneal ulcers or as vesi- malaise, dysuria, and inguinal lymphadenopathy. Complica- cles on the eyelids. With recurrent keratitis, there may be pro- tions include extragenital lesions (∼20% of cases) and aseptic gressive involvement of the corneal stroma, with permanent meningitis (∼10% of cases). Viral secretion persists for about opacification and blindness. HSV infections are second only 3 weeks. to trauma as a cause of corneal blindness in the United States. Because of the antigenic cross-reactivity between HSV-1 and HSV-2, preexisting immunity provides some protection C. Genital Herpes against heterotypic infection. An initial HSV-2 infection in a Genital disease is more often caused by HSV-2, although person already immune to HSV-1 tends to be less severe. HSV-1 can also cause clinical episodes of genital herpes. Recurrences of genital herpetic infections are common Primary genital herpes infections can be severe, with ill- and tend to be mild. A limited number of vesicles appear and ness lasting about 3 weeks. Genital herpes is characterized heal in about 10 days. Virus is shed for only a few days. Some by vesiculoulcerative lesions of the penis of the male or of recurrences are asymptomatic with anogenital shedding last- the cervix, vulva, vagina, and perineum of the female. The ing less than 24 hours. Whether a recurrence is symptomatic Riedel_CH33_p473-p498.indd 479 04/04/19 5:02 PM  480   SECTION IV  Virology or asymptomatic, a person shedding virus can transmit the the central nervous system. The worst prognosis (∼80% mor- infection to sexual partners. tality rate) applies to infants with disseminated infection, many of whom develop encephalitis. The cause of death of D. Skin Infections babies with disseminated disease is usually viral pneumoni- Intact skin is resistant to HSV, so cutaneous HSV infections tis or intravascular coagulopathy. Many survivors of severe are uncommon in healthy persons. Localized lesions caused infections are left with permanent neurologic impairment. by HSV-1 or HSV-2 may occur in abrasions that become con- taminated with the virus (traumatic herpes). These lesions G. Infections in Immunocompromised Hosts are seen on the fingers of dentists and hospital personnel Immunocompromised patients are at increased risk of (herpetic whitlow) and on the bodies of wrestlers (herpes developing severe HSV infections. These include patients gladiatorum). immunosuppressed by disease or therapy (especially those Cutaneous infections are often severe and life threaten- with deficient cellular immunity) and individuals with ing when they occur in individuals with disorders of the skin, malnutrition. Renal, cardiac, and bone marrow transplant such as eczema or burns, that permit extensive local viral rep- recipients are at particular risk for severe herpes infections. lication and spread. Eczema herpeticum is a primary infec- Patients with hematologic malignancies and patients with tion, usually with HSV-1, in a person with chronic eczema. In AIDS have more frequent and more severe HSV infections. rare instances, the illness may be fatal. Herpes lesions may spread and involve the respiratory tract, esophagus, and intestinal mucosa. Malnourished children are E. Meningitis/Encephalitis prone to fatal disseminated HSV infections. In most cases, the A severe form of meningitis or encephalitis may be produced disease reflects reactivation of latent HSV infection. by herpesvirus. HSV-1 infections are considered the most common cause of sporadic, fatal encephalitis in the United States. The disease carries a high mortality rate, and those Immunity who survive often have residual neurologic defects. About Many newborns acquire passively transferred maternal anti- half of patients with HSV encephalitis appear to have primary bodies. These antibodies are lost during the first 6 months infections, and the rest appear to have recurrent infection. of life, and the period of greatest susceptibility to primary herpes infection occurs between ages 6 months and 2 years. F. Neonatal Herpes Transplacentally acquired antibodies from the mother are not totally protective against infection of newborns, but they HSV infection of the newborn may be acquired in utero, dur- seem to ameliorate infection if not prevent it. HSV-1 antibod- ing birth, or after birth. The mother is the most common ies begin to appear in the population in early childhood; by source of infection in all cases. Neonatal herpes is estimated adolescence, they are present in most persons. Antibodies to to occur in about 1 in 5000 deliveries per year. The newborn HSV-2 rise during the age of adolescence and sexual activity. infant seems to be unable to limit the replication and spread During primary infections, IgM antibodies appear tran- of HSV and has a propensity to develop severe disease. siently and are followed by IgG and IgA antibodies that per- The most common route of infection (∼75% of cases) is sist for long periods. The more severe the primary infection for HSV to be transmitted to a newborn during birth by con- or the more frequent the recurrences, the greater the level of tact with herpetic lesions in the birth canal. To avoid infec- antibody response. However, the pattern of antibody response tion, delivery by cesarean section has been used in pregnant has not correlated with the frequency of disease recurrence. women with genital herpes lesions. However, many fewer Cell-mediated immunity and nonspecific host factors (natu- cases of neonatal HSV infection occur than cases of recurrent ral killer cells, interferon) are important in controlling both genital herpes, even when the virus is present at term. primary and recurrent HSV infections. Neonatal herpes can be acquired postnatally by exposure After recovery from a primary infection (inapparent, to either HSV-1 or HSV-2. Sources of infection include fam- mild, or severe), the virus is carried in a latent state in the ily members and hospital personnel who are shedding virus. presence of antibodies. These antibodies do not prevent rein- About 75% of neonatal herpes infections are caused by HSV-2. fection or reactivation of latent virus but may modify subse- There do not appear to be any differences between the nature quent disease. and severity of neonatal herpes in premature or full-term infants, in infections caused by HSV-1 or HSV-2, or in disease when virus is acquired during delivery or postpartum. Laboratory Diagnosis Neonatal herpes infections are almost always symptom- atic. The overall mortality rate of untreated disease is 50%. A. Molecular Detection Babies with neonatal herpes exhibit three categories of dis- Polymerase chain reaction (PCR) assays can be used to detect ease: (1) lesions localized to the skin, eye, and mouth; (2) virus in vesicle swabs, blood, CSF, and tissue and are sen- encephalitis with or without localized skin involvement; and sitive and specific. PCR amplification of viral DNA from (3) disseminated disease involving multiple organs, including cerebrospinal fluid is the most sensitive means of detection Riedel_CH33_p473-p498.indd 480 04/04/19 5:02 PM  CHAPTER 33 Herpesviruses   481 and is recommended for diagnosis of herpes meningitis/ The highest incidence of HSV-1 infection occurs among encephalitis. children 6 months to 3 years of age. By adulthood, 70–90% of persons have type 1 antibodies. There is high geographic B. Isolation and Identification of Virus variation in seroprevalence. Middle-class individuals in Virus culture is commonly used, particularly for diagnosis of developed countries acquire antibodies later in life than mucocutaneous disease. Virus may be isolated from herpetic those in lower socioeconomic populations. Presumably, this lesions and may also be found in respiratory samples, tissues reflects more crowded living conditions and poorer hygiene and body fluids, both during primary infection and during among the latter. The virus is spread by direct contact with asymptomatic periods. Therefore, the isolation of HSV is not infected saliva or through items contaminated with the saliva in itself sufficient evidence to indicate that the virus is the of a virus shedder. The source of infection for children is causative agent of a disease under investigation. usually an adult with a symptomatic herpetic lesion or with Inoculation of tissue cultures is used for viral isolation. asymptomatic viral shedding in saliva. HSV is relatively easy to cultivate, with cytopathic effects The frequency of recurrent HSV-1 infections varies widely typically occurring in 2–3 days. The agent is then identified among individuals. At any given time, 1–5% of normal adults by neutralization test or immunofluorescence staining with are excreting virus, often in the absence of clinical symptoms. specific antiserum. Shell vial culture can be used to detect HSV-2 is typically acquired as a sexually transmitted HSV replicating within cells after 24 hours of incubation disease, so antibodies to this virus are seldom found before using fluorescent antibodies. Typing of HSV isolates may be puberty. It is estimated that there are about 40–60 million done using monoclonal antibody, sequence analysis, or by infected individuals in the United States. Antibody prevalence restriction endonuclease analysis of viral DNA. studies are complicated by the cross-reactivity between HSV types 1 and 2. Surveys using type-specific glycoprotein anti- gens recently determined that 17% of adults in the United States C. Cytopathology possess HSV-2 antibodies, with seroprevalence higher among A rapid cytologic method is to stain scrapings obtained from women than men, higher among blacks than whites, and age the base of a vesicle (eg, with Giemsa’s stain); the presence of related, reaching 56% in blacks ages 30–49 years. multinucleated giant cells indicates that herpesvirus (HSV-1, Reactivation and asymptomatic shedding occur with both HSV-2, or varicella-zoster) is present, distinguishing lesions HSV-1 and HSV-2. PCR-based studies show frequent sub- from those caused by coxsackieviruses and nonviral enti- clinical reactivations in immunocompetent hosts that often ties. A more sensitive technique is direct fluorescent antigen last less than 12 hours. Both symptomatic and asymptomatic detection on slides containing virally infected cells. infections provide a reservoir of virus for transmission to sus- ceptible persons. Studies have estimated that transmission of D. Serology genital herpes in more than 50% of cases resulted from sexual Antibodies appear in 4–7 days after infection and reach a contact in the absence of lesions or symptoms. peak in 2–4 weeks. They persist with minor fluctuations for Maternal genital HSV infections pose risks to both the the life of the host. Detection methods available include neu- mother and the fetus. Rarely, pregnant women may develop tralization, immunofluorescence, and enzyme-linked immu- disseminated disease after primary infection, with a high nosorbent assay. mortality rate. Primary infection before 20 weeks of gesta- The diagnostic value of serologic assays is limited by the tion is associated with spontaneous abortion. The fetus may multiple antigens shared by HSV-1 and HSV-2. There may also acquire infection as a result of viral shedding from recur- be some heterotypic anamnestic responses to VZV in persons rent lesions in the mother’s birth canal at the time of deliv- infected with HSV and vice versa. The use of HSV type-spe- ery. Estimates of the frequency of cervical shedding of virus cific antibodies allows more meaningful serologic tests. among pregnant women vary widely. Genital HSV infections increase acquisition of human immunodeficiency virus (HIV) type 1 infections due to the Epidemiology ulcerative lesions in the mucosal surface. HSV are worldwide in distribution. No animal reservoirs or vectors are involved with the human viruses. Transmission is by contact with infected secretions. The epidemiology of Treatment, Prevention, and Control HSV-1 and HSV-2 differs. Several antiviral drugs have proved effective against HSV HSV-1 primary infection typically occurs early in life infections, including acyclovir, valacyclovir, and vidarabine and is usually asymptomatic; occasionally, it produces oro- (see Chapter 30). All are inhibitors of viral DNA synthesis. pharyngeal disease (gingivostomatitis in young children, Acyclovir, a nucleoside analog, is monophosphorylated by the pharyngitis in young adults). Antibodies develop, but the HSV thymidine kinase and is then converted to the triphos- virus is not eliminated from the body; a carrier state is estab- phate form by cellular kinases. The acyclovir triphosphate lished that lasts throughout life and is punctuated by tran- is efficiently incorporated into viral DNA by the HSV poly- sient recurrent attacks of herpes. merase, where it then prevents chain elongation. The drugs Riedel_CH33_p473-p498.indd 481 04/04/19 5:02 PM  482   SECTION IV  Virology may suppress clinical manifestations, shorten time to heal- in regional lymph nodes, primary viremia spreads virus and ing, and reduce recurrences of genital herpes. However, HSV leads to replication in the liver and spleen. Secondary viremia remains latent in sensory ganglia. Drug-resistant virus strains involving infected mononuclear cells transports virus to the may emerge. skin, where the typical rash develops. Swelling of epithelial Newborns and persons with eczema should be protected cells, ballooning degeneration, and the accumulation of tis- from exposure to persons with active herpetic lesions. sue fluids result in vesicle formation (Figure 33-6). Patients with genital herpes should be counseled that Varicella-zoster virus replication and spread are limited asymptomatic shedding is frequent and that the risk of trans- by host humoral and cellular immune responses. Interferon is mission can be reduced by antiviral therapy and condom usage. likely involved also. It has been shown that a varicella-zoster Experimental vaccines of various types are being devel- virus-encoded protein, ORF61, antagonizes the β-interferon oped. One approach is to use purified glycoprotein antigens pathway. This presumably contributes to the pathogenesis of found in the viral envelope, expressed in a recombinant sys- viral infection. tem. Such vaccines might be helpful for the prevention of primary infections. A promising recombinant HSV-2 glyco- B. Herpes Zoster protein vaccine failed to prevent herpesvirus infections in a The skin lesions of herpes zoster are histopathologically iden- large clinical trial in 2010. tical to those of varicella. There is also an acute inflammation of the sensory nerves and ganglia. Often only a single gan- glion may be involved. As a rule, the distribution of lesions in VARICELLA-ZOSTER VIRUS the skin corresponds closely to the areas of innervation from an individual dorsal root ganglion. Varicella (chickenpox) is a mild, highly contagious disease, It is not clear what triggers reactivation of latent VZV chiefly of children, characterized clinically by a generalized infections in ganglia. It is believed that waning immunity vesicular eruption of the skin and mucous membranes. The allows viral replication to occur in a ganglion, causing intense disease may be severe in adults and in immunocompromised inflammation and pain. Virus travels down the nerve to the individuals. skin and induces vesicle formation. Cell-mediated immunity Herpes zoster (shingles) is a sporadic, incapacitating dis- is probably the most important host defense in containment ease of elderly or immunocompromised individuals that is of VZV. Reactivations are sporadic and recur infrequently. characterized by pain and vesicular rash limited in distribu- tion to the skin innervated by a single sensory ganglion. The lesions are similar to those of varicella. Both diseases are caused by the same virus. Whereas Clinical Findings varicella is the acute disease that follows primary contact A. Varicella with the virus, zoster is the response of the partially immune Subclinical varicella is unusual. The incubation period of host to reactivation of varicella virus present in latent form in typical disease is 10–21 days. Malaise and fever are the earli- neurons in sensory ganglia. est symptoms, soon followed by the rash, first on the trunk and then on the face, the limbs, and the buccal and pharyn- geal mucosa in the mouth. Successive fresh vesicles appear Properties of the Virus in crops, so that all stages of macules, papules, vesicles, and Varicella-zoster virus is morphologically identical to HSV. It crusts may be seen at one time (Figure 33-7). The rash lasts has no animal reservoir. The virus propagates in cultures of about 5 days, and most children develop several hundred skin human embryonic tissue and produces typical intranuclear lesions. inclusion bodies (see Figure 33-3B). Cytopathic changes are Complications are rare in normal children, and the mor- more focal and spread much more slowly than those induced tality rate is very low. Encephalitis does occur in rare cases by HSV. Infectious virus remains strongly cell associated, and and can be life threatening. Survivors of varicella encephalitis serial propagation is more easily accomplished by passage of may be left with permanent sequelae. In neonatal varicella, infected cells than of tissue culture fluids. the infection is contracted from the mother just before or The same virus causes chickenpox and zoster. Viral iso- after birth but without sufficient immune response to modify lates from the vesicles of chickenpox or zoster patients exhibit the disease. Virus is often widely disseminated and may prove no significant genetic variation. Inoculation of zoster vesicle fatal. Cases of congenital varicella syndrome after maternal fluid into children produces chickenpox. cases of chickenpox during pregnancy have been described. Varicella pneumonia is rare in healthy children but is the most common complication in neonates, adults, and immu- Pathogenesis and Pathology nocompromised patients. It is responsible for many varicella- A. Varicella related deaths. The route of infection is the mucosa of the upper respiratory Immunocompromised patients are at increased risk of tract or the conjunctiva (Figure 33-5). After initial replication complications of varicella, including those with malignancies, Riedel_CH33_p473-p498.indd 482 04/04/19 5:02 PM  CHAPTER 33 Herpesviruses   483 1 Varicella-zoster virus is inhaled; infects mucosal cells in nose and throat. 2 The virus infects nearby lymph nodes, replicates, and enters the bloodstream 1 (primary viremia). 7 3 Infection of other body cells occurs, 5 6 with replication in liver and spleen, resulting in secondary viremia. 2 4 The virus causes successive crops 3 of skin lesions, which evolve into blisters and crusts. 5 Immune system eliminates the infection 4 except for some virions that establish latent infections inside nerve cells. 7 6 If immunity wanes with age or other reason, the virus persisting in the nerve ganglia can infect the skin, causing herpes zoster. 7 Transmission to others occurs from respiratory secretions and skin. FIGURE 33-5 The pathogenesis of primary infection with varicella-zoster virus. The incubation period lasts from 10 to 21 days. Secondary viremia results in the transport of virus to skin and respiratory mucosal sites, where replication in epidermal cells causes the characteristic rash (chickenpox). Varicella-zoster virus-specific immunity is required to terminate viral replication. The virus gains access to cells of the trigeminal and dorsal root ganglia during primary infection and establishes latency. (Reproduced with permission from Nester EW, Anderson DG, Roberts CE, et al: Microbiology: A Human Perspective, 6th ed. McGraw-Hill, 2009, p. 293. © McGraw-Hill Education.) A B FIGURE 33-6 Characteristic histologic changes of varicella- zoster virus infection. Punch biopsies of varicella-zoster virus vesicles were fixed and stained with hematoxylin and eosin. A: Early infection showing “balloon degeneration” of cells with basophilic nuclei and marginated chromatin (reduced from 480×). B: Later infection showing eosinophilic intranuclear inclusions surrounded by wide clear zones (reduced from 480×). C: Multinucleated giant cell in the roof of a varicella vesicle (reduced from 480×). D: Low- power view of an early vesicle showing separation of the epidermis (acantholysis), dermal edema, and mononuclear cell infiltration (reduced from 40×). (Reproduced with permission from Gelb LD: Varicella-zoster virus. In Fields BN, Knipe DM [editors-in-chief]. C D Virology, 2nd ed. Raven Press, 1990.) Riedel_CH33_p473-p498.indd 483 04/04/19 5:02 PM  484   SECTION IV  Virology develops in healthy young adults. It usually starts with severe pain in the area of skin or mucosa supplied by one or more groups of sensory nerves and ganglia and is often unilateral. Within a few days after onset, a crop of vesicles appears over the skin supplied by the affected nerves. The trunk, head, and neck are most commonly affected (Figure 33-8), with the oph- thalmic division of the trigeminal nerve involved in 10–15% of cases. The most common complication of zoster in elderly adults is postherpetic neuralgia—protracted pain that may continue for months. It is especially common after ophthalmic zoster. Visceral disease, especially pneumonia, is responsible for deaths that occur in immunosuppressed patients with zos- ter (90%) con- EBV is commonly transmitted by infected saliva and initi- tain EBV DNA and express EBNA1 antigen. In other parts ates infection in the oropharynx. Viral replication occurs of the world, only about 20% of Burkitt lymphomas contain in epithelial cells (or surface B lymphocytes) of the pharynx EBV DNA. It is speculated that EBV may be involved at an and salivary glands. Many people shed low levels of virus for early stage in Burkitt lymphoma by immortalizing B cells. weeks to months after infection. Infected B cells spread the Malaria, a recognized cofactor, may foster enlargement of the infection from the oropharynx throughout the body. In nor- pool of EBV-infected cells. Finally, there are characteristic mal individuals, most virus-infected cells are eliminated, but chromosome translocations that involve immunoglobulin small numbers of latently infected lymphocytes persist for genes and result in deregulation of expression of the c-myc the lifetime of the host (one in 105–106 B cells). proto-oncogene. Primary infections in children are usually subclinical, Nasopharyngeal carcinoma is a cancer of epithelial cells but if they occur in young adults, acute infectious mono- and is common in males of Chinese and southeastern Asian nucleosis often develops. Mononucleosis is a polyclonal origin. EBV DNA is regularly found in nasopharyngeal carci- stimulation of lymphocytes. EBV-infected B cells synthesize noma cells, and patients have high levels of antibody to EBV. immunoglobulin. Autoantibodies are typical of the disease, EBNA1 and LMP1 are expressed. Genetic and environmental with heterophil antibody that reacts with antigens on sheep factors are believed to be important in the development of erythrocytes detectable in acute cases. nasopharyngeal carcinoma. Immunodeficient patients are susceptible to EBV- B. Reactivation from Latency induced lymphoproliferative diseases that may be fatal. From 1% to 10% of transplant patients develop an EBV-associated Reactivations of EBV latent infections can occur, as evi- lymphoproliferative disorder, often when experiencing a pri- denced by increased levels of virus in saliva and of DNA in mary infection. Aggressive monoclonal B-cell lymphomas blood cells. These are usually clinically silent. Immunosup- may subsequently develop. pression is known to reactivate infection, sometimes with AIDS patients are susceptible to EBV-associated lym- serious consequences. phomas and oral hairy leukoplakia, a wart-like growth that develops on the tongue; it is an epithelial focus of EBV rep- Clinical Findings lication. Virtually all central nervous system non-Hodgkin Most primary infections in children are asymptomatic. In lymphomas are associated with EBV, but fewer than 50% adolescents and young adults, the classic syndrome associ- of systemic lymphomas are EBV positive. In addition, EBV ated with primary infection is infectious mononucleosis is associated with classic Hodgkin disease, with the viral (∼50% of infections). EBV is also associated with several types genome detected in the malignant Reed-Sternberg cells in up of cancer. to 50% of cases. A. Infectious Mononucleosis Immunity After an incubation period of 30–50 days, symptoms of head- EBV infections elicit an intense immune response consisting ache, fever, malaise, fatigue, and sore throat occur. Enlarged of antibodies against many virus-specific proteins, a number lymph nodes and spleen are characteristic. Some patients of cell-mediated responses, and secretion of lymphokines. develop signs of hepatitis. Cell-mediated immunity and cytotoxic T cells are impor- The typical illness is self-limited and lasts for 2–4 weeks. tant in limiting primary infections and controlling chronic During the disease, there is an increase in the number of infections. circulating white blood cells, with a predominance of lym- Serologic testing to determine the pattern of specific phocytes. Many of these are large, atypical T lymphocytes. antibodies to different classes of EBV antigens is the usual Low-grade fever and malaise may persist for weeks to months means of ascertaining a patient’s status with regard to EBV after acute illness. Complications are rare in normal hosts. infection. Riedel_CH33_p473-p498.indd 487 04/04/19 5:02 PM  488   SECTION IV  Virology Laboratory Diagnosis Symptoms A. Molecular Detection Primary Reactivation PCR assays for EBV viral DNA can detect virus in blood, body fluids, and tissues. Quantitative PCR methods can determine viral load and are used to monitor for early development Antibody titer of post-transplant lymphoproliferative disorder (PTLD) in transplant patients. Testing of plasma will detect circulat- ing viremia (often associated with PTLD progression), while VCA lgG whole blood can detect EBV integrated into WBC genomes or VCA lgM latent infections. Nucleic acid hybridization can detect EBV EBNA lgG Heterophile in patient tissues. EBER RNAs are abundantly expressed in EA both latently infected and lytically infected cells and provide a useful diagnostic target for detection of EBV-infected cells ~1 month ~2 months Years by hybridization. Viral antigens can be demonstrated directly Time after infection in lymphoid tissues and in nasopharyngeal carcinomas. Dur- FIGURE 33-10 Typical pattern of antibody formation to ing the acute phase of infection, about 1% of circulating Epstein-Barr virus (EBV)-specific antigens after a primary infection. lymphocytes will contain EBV markers; after recovery from Individuals with recent infection have immunoglobulin M (IgM) infection, about one in 1 million B lymphocytes will carry and IgG antibodies to the viral capsid antigen (VCA IgM, VCA IgG); the virus. only the IgG antibodies persist for years. Transient heterophil antibodies develop that can agglutinate sheep cells. Antibodies to early antigens (EA) develop in many patients and persist for several B. Isolation of Virus months. Several weeks after acute infection, antibodies to EBV EBV can be isolated from saliva, peripheral blood, or lym- nuclear antigens (EBNA) and membrane antigen appear and persist phoid tissue by immortalization of normal human lympho- for life. (Reprinted from Gulley ML, Tang W: Laboratory assays for cytes, usually obtained from umbilical cord blood. This assay Epstein-Barr virus-related disease. J Mol Diagn 2008;10:279–292 with is laborious and time consuming (6–8 weeks), requires spe- permission from the American Society for Investigative Pathology cialized facilities, and is seldom performed. It is also possible and the Association for Molecular Pathology.) to culture “spontaneously transformed” B lymphocytes from virus-infected patients. Any recovered immortalizing agent is infection and indicates immunity. Early antigen antibodies confirmed as EBV by detection of EBV DNA or virus-specific are generally evidence of current viral infection, although antigens in the immortalized lymphocytes. such antibodies are often found in patients with Burkitt lymphoma or nasopharyngeal carcinoma. Antibodies to the C. Serology EBNA antigens reveal past infection with EBV, although Common serologic procedures for detection of EBV antibod- detection of a rise in anti-EBNA antibody titer suggests a pri- ies include enzyme-linked immunosorbent assays, immu- mary infection. Not all persons develop antibody to EBNA. noblot assays, and indirect immunofluorescence tests using EBV-positive lymphoid cells. The typical pattern of antibody responses to EBV-specific Epidemiology antigens after a primary infection is shown in Figure 33-10. EBV is common in all parts of the world, with more than 90% Early in acute disease, a transient rise in IgM antibodies to of adults being seropositive. It is transmitted primarily by viral capsid antigen (VCA) occurs, replaced within weeks by contact with oropharyngeal secretions. In developing areas, IgG antibodies to this antigen, which persist for life. Slightly infections occur early in life; more than 90% of children are later, antibodies to the early antigen (EA) develop that persist infected by age 6 years. These infections in early childhood for several months. Several weeks after acute infection, anti- usually occur without any recognizable disease. The inap- bodies to EBNA and the membrane antigen arise and persist parent infections result in permanent immunity to infectious throughout life. mononucleosis. In industrialized nations, more than 50% of The less-specific heterophil agglutination test may be EBV infections are delayed until late adolescence and young used to diagnose acute EBV infections. In the course of infec- adulthood. In almost half of cases, the infection is mani- tious mononucleosis, most patients develop transient hetero- fested by infectious mononucleosis. There are an estimated phil antibodies that agglutinate sheep cells. Commercially 100,000 cases of infectious mononucleosis annually in the available spot tests are convenient. United States. Serologic tests for EBV antibodies require some interpre- tation. The presence of antibody of the IgM type to the viral capsid antigen is indicative of current infection. Antibody of Prevention, Treatment, and Control the IgG type to the viral capsid antigen is a marker of past There is no EBV vaccine available. Riedel_CH33_p473-p498.indd 488 04/04/19 5:02 PM  CHAPTER 33 Herpesviruses   489 Acyclovir reduces EBV shedding from the oropharynx during the period of drug administration, but it does not affect the number of EBV-immortalized B cells. Acyclovir has no effect on the symptoms of mononucleosis and is of no proved benefit in the treatment of EBV-associated lympho- mas in immunocompromised patients. Adoptive transfer of EBV-reactive T cells shows promise as a treatment for EBV-related lymphoproliferative disease. CYTOMEGALOVIRUS CMV is a ubiquitous herpesvirus that is a common cause of human disease. CMV is the most common cause of congeni- tal infection, which can lead to severe abnormalities. Inappar- ent infection is common during childhood and adolescence. Severe CMV infections are frequently found in adults who are immunosuppressed. FIGURE 33-11 Massively enlarged “cytomegalic” cells typical of CMV infections can manifest as cytomegalic inclusion cytomegalovirus infection present in the lung of a premature infant disease, whose name derives from the propensity for massive who died of disseminated cytomegalovirus disease. (Courtesy of GJ Demmler.) enlargement of CMV-infected cells with intranuclear inclu- sion bodies. Multinucleated cells are seen. Many affected cells become greatly enlarged. Inclusion-bearing cytomegalic cells can be Properties of the Virus found in samples from infected individuals (Figure 33-11). CMV has the largest genetic content of the human herpesvi- ruses. Its DNA genome (240 kbp) is significantly larger than that of HSV. Only a few of the many proteins encoded by the Pathogenesis and Pathology virus (∼200) have been characterized. One, a cell surface gly- A. Normal Hosts coprotein, acts as an Fc receptor that can nonspecifically bind the Fc portion of immunoglobulins. This may help infected CMV may be transmitted from person to person in several cells evade immune elimination by providing a protective different ways, all requiring close contact with virus-bearing coating of irrelevant host immunoglobulins. material. There is a 4- to 8-week incubation period in nor- The major immediate-early promoter–enhancer of CMV mal older children and adults after viral exposure. The virus is one of the strongest known enhancers because of the con- causes a systemic infection; it has been isolated from lung, centration of binding sites for cellular transcription factors. liver, esophagus, colon, kidneys, monocytes, and T and B It is used experimentally to support high-level expression of lymphocytes. The disease can manifest as an infectious foreign genes. mononucleosis-like syndrome, although most CMV infec- Many genetically different strains of CMV are circulat- tions are subclinical. Similar to all herpesviruses, CMV ing in the human population. The strains are sufficiently establishes lifelong latent infections. Virus can be shed inter- related antigenically, however, so that strain antigenic dif- mittently from the pharynx and in the urine for months to ferences are probably not important determinants in human years after primary infection (Figure 33-12). Prolonged CMV disease. infection of the kidney does not seem to be deleterious in nor- CMVs are very species-specific and cell-type specific. All mal persons. Salivary gland involvement is common and is attempts to infect animals with human CMV have failed. A probably chronic. number of animal CMVs exist, all of them species specific. Cell-mediated immunity is depressed with primary Human CMV replicates in vitro only in human fibro- infections (see Figure 33-12), and this may contribute to the blasts, although the virus is often isolated from epithelial persistence of viral infection. It may take several months for cells of the host. CMV replicates slowly in cultured cells, with cellular responses to recover. growth proceeding more slowly than that of HSV. Very little virus becomes cell free; infection is spread primarily from B. Immunosuppressed Hosts cell to cell. It may take several weeks for an entire monolayer Primary CMV infections in immunosuppressed hosts are of cultured cells to become involved. much more severe than in normal hosts. Individuals at great- CMV produces a characteristic cytopathic effect (see est risk for CMV disease are those receiving hemapoietic Figure 33-3C). Perinuclear cytoplasmic inclusions form in stem cell and solid organ transplants, those with malignant addition to the intranuclear inclusions typical of herpesviruses. tumors who are receiving chemotherapy, and those with Riedel_CH33_p473-p498.indd 489 04/04/19 5:02 PM  490   SECTION IV  Virology Atypical lymphocytes Clinical Incubation period Hepatic dysfunction 4–8 weeks Fever Lymphocytosis Blood +++ − − − − − − Virologic Throat + + + + + − − − − Urine + + + + + + + + + − − − Immunologic Antibody IgG Ab titers Nt Ab IgM Ab CF Ab Normal LTR Mitogens CMV Ag Suppressor T cells (n) Normal Helper Birth 1 2 3 4 5 6 2 3 4 1 2 3 Weeks Months Years A Time after onset of symptoms CNS damage (brain, perceptual organs) Clinical findings Clinical Pete Hepatosplenomegaly c