Review of Medical Microbiology and Immunology, 13th Edition

38. DNA Nonenveloped Viruses

CHAPTER CONTENTS

Adenoviruses

Papillomaviruses

Parvoviruses

Polyomaviruses

Self-Assessment Questions

Summaries of Organisms

Practice Questions: USMLE & Course Examinations

ADENOVIRUSES

Diseases

Adenoviruses cause a variety of upper and lower respiratory tract diseases such as pharyngitis, conjunctivitis (“pink eye”), the common cold, and pneumonia. Keratoconjunctivitis, hemorrhagic cystitis, and gastroenteritis also occur. Some adenoviruses cause sarcomas in rodents. Table 38–1 describes some of the important clinical features of adenoviruses and compares them with features of the other two medically important viruses in this chapter, human papillomavirus (HPV) and parvovirus B19.

TABLE 38–1 Clinical Features of DNA Nonenveloped Viruses

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Important Properties

Adenoviruses are nonenveloped viruses with double-stranded linear DNA and an icosahedral nucleocapsid. They are the only viruses with a fiber protruding from each of the 12 vertices of the capsid. The fiber is the organ of attachment and is a hemagglutinin. When purified free of virions, the fiber is toxic to human cells.

There are 41 known antigenic types; the fiber protein is the main type-specific antigen. All adenoviruses have a common group-specific antigen located on the hexon protein.

Certain serotypes of human adenoviruses (especially 12, 18, and 31) cause sarcomas at the site of injection in laboratory rodents such as newborn hamsters. There is no evidence that adenoviruses cause tumors in humans.

Summary of Replicative Cycle

After attachment to the cell surface via its fiber, the virus penetrates and uncoats, and the viral DNA moves to the nucleus. Host cell DNA-dependent RNA polymerase transcribes the early genes, and splicing enzymes remove the RNA representing the introns, resulting in functional mRNA. (Note that introns and exons, which are common in eukaryotic DNA, were first described for adenovirus DNA.) Early mRNA is translated into nonstructural proteins in the cytoplasm. After viral DNA replication in the nucleus, late mRNA is transcribed and then translated into structural virion proteins. Viral assembly occurs in the nucleus, and the virus is released by lysis of the cell, not by budding.

Transmission & Epidemiology

Adenoviruses are transmitted by several mechanisms: aerosol droplet, fecal–oral route, and direct inoculation of conjunctivas by tonometers or fingers. The fecal–oral route is the most common mode of transmission among young children and their families. Many species of animals are infected by strains of adenovirus, but these strains are not pathogenic for humans.

Adenovirus infections are endemic worldwide, but outbreaks occur among military recruits, apparently as a result of the close living conditions that facilitate transmission. Certain serotypes are associated with specific syndromes (e.g., types 3, 4, 7, and 21 cause respiratory disease, especially in military recruits; types 8 and 19 cause epidemic keratoconjunctivitis; types 11 and 21 cause hemorrhagic cystitis; and types 40 and 41 cause infantile gastroenteritis).

Pathogenesis & Immunity

Adenoviruses infect the mucosal epithelium of several organs (e.g., the respiratory tract [both upper and lower], the gastrointestinal tract, and the conjunctivas). Immunity based on neutralizing antibody is type-specific and lifelong.

In addition to acute infection leading to death of the cells, adenoviruses cause a latent infection, particularly in the adenoidal and tonsillar tissues of the throat. In fact, these viruses were named for the adenoids, from which they were first isolated in 1953.

Clinical Findings

In the upper respiratory tract, adenoviruses cause such infections as pharyngitis, pharyngoconjunctival fever, and acute respiratory disease, characterized by fever, sore throat, coryza (runny nose), and conjunctivitis. In the lower respiratory tract, they cause bronchitis and atypical pneumonia. Hematuria and dysuria are prominent in hemorrhagic cystitis. Gastroenteritis with nonbloody diarrhea occurs mainly in children younger than 2 years of age. Most adenovirus infections resolve spontaneously. Approximately half of all adenovirus infections are asymptomatic.

Laboratory Diagnosis

The most frequent methods of diagnosis are isolation of the virus in cell culture and detection of a fourfold or greater rise in antibody titer. Complement fixation and hemagglutination inhibition are the most important serologic tests.

Treatment

There is no antiviral therapy.

Prevention

Three live, nonattenuated vaccines against serotypes 4, 7, and 21 are available but are used only by the military. Each of the three vaccines is monovalent (i.e., each contains only one serotype). The viruses are administered separately because they interfere with each other when given together. The vaccines are delivered in an enteric-coated capsule, which protects the live virus from inactivation by stomach acid. The virus infects the gastrointestinal tract, where it causes an asymptomatic infection and induces immunity to respiratory disease. This vaccine is not available for civilian use.

Epidemic keratoconjunctivitis is an iatrogenic disease, preventable by strict asepsis and hand washing by health care personnel who examine eyes.

PAPILLOMAVIRUSES

Diseases

Human papillomavirus causes papillomas, which are benign tumors of squamous cells (e.g., warts on the skin). Some HPV types, especially types 16 and 18, cause carcinoma of the cervix, penis, and anus.

Important Properties

Papillomaviruses are nonenveloped viruses with double-stranded circular DNA and an icosahedral nucleocapsid. Two of the early genes, E6 and E7, are implicated in carcinogenesis. They encode proteins that inactivate proteins encoded by tumor suppressor genes in human cells (e.g., the p53 gene and the retinoblastoma [RB] gene, respectively). Inactivation of the p53 and RB proteins is an important step in the process by which a normal cell becomes a cancer cell.

There are at least 100 types of papillomaviruses, classified primarily on the basis of DNA restriction fragment analysis. There is a pronounced predilection of certain types to infect certain tissues. For example, skin warts are caused primarily by HPV-1 through HPV-4, whereas genital warts are usually caused by HPV-6 and HPV-11. Approximately 30 types of HPV infect the genital tract.

Summary of Replicative Cycle

Little is known of the specifics of viral replication, because the virus grows poorly, if at all, in cell culture. In human tissue, infectious virus particles are found in the terminally differentiated squamous cells rather than in the basal cells. Note that HPV initially infects the cells of the basal layer in the skin, but no virus is produced by those cells. Rather, infectious virions are produced by squamous cells on the surface, which enhances the likelihood that efficient transmission will occur.

In malignant cells, viral DNA is integrated into host cell DNA in the vicinity of cellular proto-oncogenes, and E6 and E7 are overexpressed. However, in latently infected, nonmalignant cells, the viral DNA is episomal, and E6 and E7 are not overexpressed. This difference occurs because another early gene, E2, controls E6 and E7 expression. The E2 gene is functional when the viral DNA is episomal but is inactivated when it is integrated.

Transmission & Epidemiology

Papillomaviruses are transmitted primarily by skin-to-skin contact and by genital contact. Genital warts are among the most common sexually transmitted diseases. Skin warts are more common in children and young adults and tend to regress in older adults. HPV transmitted from an infected mother to the neonate during childbirth causes warts in the mouth and in the respiratory tract, especially on the larynx, of the infant. Many species of animals are infected with their own types of papillomaviruses, but these viruses are not an important source of human infection.

Pathogenesis & Immunity

Papillomaviruses infect squamous epithelial cells and induce within those cells a characteristic cytoplasmic vacuole. These vacuolated cells, called koilocytes, are the hallmark of infection by these viruses. Most warts are benign and do not progress to malignancy. However, HPV infection is associated with carcinoma of the uterine cervix and penis. The proteins encoded by viral genes E6 and E7 interfere with the growth-inhibitory activity of the proteins encoded by the p53 and RB tumor suppressor genes and thereby contribute to oncogenesis by these viruses. The E6 and E7 proteins of HPV-16 bind more strongly to p53 and RB proteins than the E6 and E7 proteins of HPV types not implicated in carcinomas—a finding that explains why HPV-16 causes carcinomas more frequently than the other types of HPV.

Both cell-mediated immunity and antibody are induced by viral infection and are involved in the spontaneous regression of warts. Immunosuppressed patients (e.g., patients with acquired immunodeficiency syndrome [AIDS]) have more extensive warts, and women infected with human immunodeficiency virus (HIV) have a very high rate of carcinoma of the cervix.

Clinical Findings

Papillomas of various organs are the predominant finding. These papillomas are caused by specific HPV types. For example, skin and plantar warts (Figure 38–1) are caused primarily by HPV-1 through HPV-4, whereas genital warts (condylomata acuminata) (Figure 38–2) are caused primarily by HPV-6 and HPV-11. HPV-6 and HPV-11 also cause respiratory tract papillomas, especially laryngeal papillomas, in young children.

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FIGURE 38–1 Papillomas (warts) on finger—note dry, raised verrucous lesions caused by human papillomavirus. (Reproduced with permission from Wolff K, Johnson R. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill, 2009. Copyright © 2009 by The McGraw-Hill Companies, Inc.)

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FIGURE 38–2 Papillomas (warts) on penis (condylomata acuminata)—note dry, raised verrucous lesions caused by human papillomavirus. (Reproduced with permission from Wolff K, Johnson R. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill, 2009. Copyright © 2009 by The McGraw-Hill Companies, Inc.)

Carcinoma of the uterine cervix, the penis, and the anus, as well as premalignant lesions called intraepithelial neoplasia, are associated with infection by HPV-16 and HPV-18. The premalignant lesions are named for the organ affected (e.g., cervical intraepithelial neoplasia [CIN], penile intraepithelial neoplasia [PIN]). Occult premalignant lesions of the cervix and penis can be revealed by applying acetic acid to the tissue. HPV-16 is also implicated as the cause of oral cancers.

Laboratory Diagnosis

Infections are usually diagnosed clinically. The presence of koilocytes in the lesions indicates HPV infection. A polymerase chain reaction (PCR)–based test can be used to detect the presence of the DNA of 14 high-risk genotypes, including HPV-16 and HPV-18.

Diagnostic tests based on detection of antibodies in a patient’s serum or on isolation of the virus from a patient’s tissue are not used.

Treatment & Prevention

The usual treatment for genital warts is podophyllin; alpha interferon is also effective and is better at preventing recurrences than are non-antiviral treatments. Liquid nitrogen is commonly used for skin warts. Plantar warts can be removed surgically or treated with salicylic acid topically. Cidofovir may be useful in the treatment of severe HPV infections.

There are two vaccines against HPV. Gardasil, a recombinant vaccine against four types of HPV, contains the capsid proteins of types 6 and 11, which cause genital warts, and types 16 and 18, which are the two most common causes of cervical, penile, and anal carcinoma. Cervarix is also a recombinant vaccine but contains the proteins only of types 16 and 18. Cervarix contains an adjuvant called AS04 that stimulates Toll-like receptors and thereby enhances antibody production. HPV immunizations have no effect on existing papillomas.

The role of cesarean section in preventing transmission of HPV from a mother with genital warts to her newborn is uncertain. Circumcision reduces the risk of infection by HPV.

PARVOVIRUSES

Diseases

Parvovirus B19 causes erythema infectiosum (slapped cheek syndrome, fifth disease), aplastic anemia (especially in patients with sickle cell anemia), and fetal infections, including hydrops fetalis.

Important Properties

Parvovirus B19 is a very small (22 nm) nonenveloped virus with a single-stranded DNA genome. The genome is negative-strand DNA, but there is no virion polymerase. The capsid has icosahedral symmetry. There is one serotype.

Summary of Replicative Cycle

After adsorption to host cell receptors, the virion penetrates and moves to the nucleus, where replication occurs. The single-stranded genome DNA has “hairpin” loops at both of its ends that provide double-stranded areas for the cellular DNA polymerase to initiate the synthesis of the progeny genomes. The viral mRNA is synthesized by cellular RNA polymerase from the double-stranded DNA intermediate. The progeny virions are assembled in the nucleus. B19 virus replicates only when a cell is in S phase, which explains why the virus replicates in red cell precursors but not in mature red cells.

Transmission & Epidemiology

B19 virus is transmitted primarily by the respiratory route; transplacental transmission also occurs. Blood donated for transfusions also can transmit the virus. B19 virus infection occurs worldwide, and about half the people in the United States older than 18 years of age have antibodies to the virus. Humans are the natural reservoir; animals are not a source of human infection.

Pathogenesis & Immunity

B19 virus infects primarily two types of cells: red blood cell precursors (erythroblasts) in the bone marrow, which accounts for the aplastic anemia, and endothelial cells in the blood vessels, which accounts, in part, for the rash associated with erythema infectiosum. Immune complexes composed of virus and IgM or IgG also contribute to the pathogenesis of the rash and to the arthritis that is seen in some adults infected with B19 virus. Infection provides lifelong immunity against reinfection.

Hydrops fetalis manifests as massive edema of the fetus. This is secondary to congestive heart failure precipitated by severe anemia caused by the death of parvovirus B19–infected erythroblasts in the fetus.

Clinical Findings

There are five important clinical presentations.

Erythema Infectiosum (Slapped Cheek Syndrome, Fifth Disease)

This is a mild disease, primarily of childhood, characterized by a bright red rash that is most prominent on the cheeks (Figure 38–3), accompanied by low-grade fever, runny nose (coryza), and sore throat. A “lacy,” less intense, erythematous rash appears on the body. The symptoms resolve in about 1 week.

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FIGURE 38–3 Slapped cheek syndrome—note erythematous macular rash on cheeks bilaterally caused by parvovirus B19. (Courtesy of Richard P. Usatine, MD, and The Color Atlas of Family Medicine.)

The disease in children is also called fifth disease. The four other macular or maculopapular rash diseases of childhood are measles, rubella, scarlet fever, and roseola.

Aplastic Anemia

Children with chronic anemia, such as sickle cell anemia, thalassemia, and spherocytosis, can have transient but severe aplastic anemia (aplastic crisis) when infected with B19 virus. People with normal red blood cells do not have clinically apparent anemia, although their red blood cell precursors are infected.

Fetal Infections

If a woman is infected with B19 virus during the first or second trimester of pregnancy, the virus may cross the placenta and infect the fetus. Infection during the first trimester is associated with fetal death, whereas infection during the second trimester leads to hydrops fetalis. Third-trimester infections do not result in important clinical findings. B19 virus is not a common cause of congenital abnormalities, probably because the fetus dies when infected early in pregnancy.

Arthritis

Parvovirus B19 infection in adults, especially women, can cause arthritis mainly involving the small joints of the hands and feet bilaterally. It resembles rheumatoid arthritis. Other viral infections that cause an immune complex–related arthritis include hepatitis B and rubella.

Chronic B19 Infection

People with immunodeficiencies, especially HIV-infected, chemotherapy, or transplant patients, can have chronic anemia, leukopenia, or thrombocytopenia as a result of chronic B19 infection.

Laboratory Diagnosis

Fifth disease and aplastic anemia are usually diagnosed by detecting IgM antibodies. B19 virus can be isolated from throat swabs, but this is not usually done. In immunocompromised patients, antibodies may not be detectable; therefore, viral DNA in the blood can be assayed by PCR methods. Fetal infection can be determined by PCR analysis of amniotic fluid.

Treatment & Prevention

There is no specific treatment of B19 infection. Pooled immune globulins may have a beneficial effect on chronic B19 infection in patients with immunodeficiencies. There is no vaccine or chemoprophylaxis.

POLYOMAVIRUSES

There are three members of the polyomavirus family that cause disease in humans, Merkel cell polyomavirus, JC virus, and BK virus. One member, SV40 virus, is a monkey virus that infected humans when it contaminated the poliovirus vaccine but has not caused human disease.

Merkel cell polyomavirus causes carcinoma of the skin and is discussed in Chapter 43. JC virus is the cause of progressive multifocal leukoencephalopathy and is discussed in Chapter 44. BK virus causes nephropathy in renal transplant patients and is discussed in Chapter 46. SV40 virus causes no detectable disease in humans but does cause sarcomas in newborn hamsters. SV40 virus is discussed as a tumor virus in Chapter 43 and as a contaminant of the poliovirus vaccine in Chapter 40.

SELF-ASSESSMENT QUESTIONS

1. Regarding adenoviruses, which one of the following statements is most accurate?

(A) Acyclovir is the drug of choice for life-threatening infections.

(B) They cause pharyngitis, pneumonia, and conjunctivitis (“pink eye”).

(C) They are often transmitted across the placenta and cause hydrocephalus in the fetus.

(D) The adenovirus vaccine is recommended for all children prior to entering first grade.

(E) Laboratory diagnosis depends on seeing multinucleated giant cells on biopsy as the virus has not been grown in cell culture.

2. Regarding human papillomavirus (HPV), which one of the following statements is most accurate?

(A) There is no vaccine available against HPV.

(B) Acyclovir is effective in preventing lesions caused by HPV but does not cure the latent state.

(C) Antigen–antibody complexes play an important role in the pathogenesis of warts caused by HPV.

(D) The early proteins of HPV play a more important role in malignant transformation than the late proteins.

(E) The diagnosis of HPV infection is usually made by detecting cytoplasmic inclusions within giant cells in the lesions.

3. Regarding parvovirus B19, which one of the following statements is most accurate?

(A) A vaccine is available that contains killed virus as the immunogen.

(B) Patients infected by parvovirus B19 can be diagnosed in the laboratory using the cold agglutinin test.

(C) Parvovirus B19 causes a severe anemia because it preferentially infects erythrocyte precursors such as erythroblasts.

(D) It commonly infects neutrophils, resulting in an immunodeficiency that predisposes to infections by pyogenic bacteria.

(E) Parvoviruses have a double-stranded DNA genome but require a DNA polymerase in the virion because they replicate in the cytoplasm.

4. A 24-year-old woman is seen by her gynecologist for a routine Pap smear. The smear shows cervical intraepithelial neoplasia grade 3 (CIN 3). You decide to examine her long-term male sexual partner. Which one of the following is the most likely finding?

(A) Condylomata lata

(B) Condylomata acuminata

(C) Penile intraepithelial neoplasia associated with HPV-6

(D) Penile intraepithelial neoplasia associated with HPV-16

ANSWERS

1. (B)

2. (D)

3. (C)

4. (D)

SUMMARIES OF ORGANISMS

Brief summaries of the organisms described in this chapter begin on page 648. Please consult these summaries for a rapid review of the essential material.

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Clinical Virology section of PART XIII: USMLE (National Board) Practice Questions starting on page 703. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.