DNA viruses dsDNA RNA viruses ss DNA always single molecule RNA viruses single or segmented Helical or icosahedron or complex (Pox,filo,etc.)

(-) rnaviruses carry RNA polymerase Enveloped viruses are more sensitive

Adenoviruses, Parvoviruses, Papillomaviruses and Polyomaviruses

Adenoviruses First isolated in 1953 in a human adenoid cell culture. Approximately 100 serotypes have been recognized, at least 47 of which infect humans. Have been classified into six subgroups (A through F).

Adenoviruses The first human adenoviruses to be identified, numbered 1 to 7, are the most common. Respiratory tract infection, conjunctivitis (pinkeye), hemorrhagic cystitis, and gastroenteritis. Several adenoviruses have oncogenic potential in animals and for this reason have been extensively studied by molecular biologists.

Structure and Replication Linear, double-stranded DNA The virions are nonenveloped icosadeltahedrons The capsid comprises 240 capsomeres, which consist of hexons and pentons. The 12 pentons, which are located at each of the vertices, have a penton base and a fiber.

Structure and Replication The fiber contains the viral attachment proteins and can act as a hemagglutinin. The pentons and fibers also carry type-specific antigens.

Electron micrograph of adenovirus virion with fibers

Pathogenesis and Immunity Capable of causing lytic (e.g., mucoepithelial cells), latent (e.g., lymphoid and adenoid cells), and transforming (hamster, not human) infections. The viral fiber proteins determine the target cell specificity.

Pathogenesis and Immunity The histologic hallmark is a dense, central intranuclear inclusion within an infected epithelial cell that consists of viral DNA and protein Resemble those seen in cells infected with cytomegalovirus, but adenovirus does not cause cellular enlargement (cytomegaly).

Histologic appearance of adenovirus-infected cells Inefficient assembly of virions yields dark basophilic nuclear inclusion bodies containing DNA, proteins, and capsids.

Infect epithelial cells lining the oropharynx, the respiratory and enteric organs

Pathogenesis and Immunity Viremia may occur after local replication of the virus, with subsequent spread to visceral organs. Has a propensity to become latent and persist in lymphoid and other tissue, such as adenoids, tonsils and Peyer's patches, and can be reactivated in immunosuppressed patients. Although certain adenoviruses (groups A and B) are oncogenic in certain rodents, adenovirus transformation of human cells has not been observed.

Epidemiology Resist drying, detergents, gastrointestinal tract secretions (acid, protease, and bile), and even mild chlorine treatment. Can be spread by the fecal-oral route, by fingers, by fomites (including towels and medical instruments), and in poorly chlorinated swimming pools.

Epidemiology Are spread mainly by respiratory or fecal-oral contact from human to human. Close interaction among people, as occurs in classrooms and military barracks, promotes spread of the virus. Most infections are asymptomatic, a feature that greatly facilitates their spread in the community. Adenoviruses 1 through 7 are the most prevalent serotypes

Clinical Syndromes Adenoviruses primarily infect children and less commonly infect adults. Disease from reactivated virus occurs in immunocompromised children and adults. Several distinct clinical syndromes are associated with adenovirus infection.

ACUTE FEBRILE PHARYNGITIS AND PHARYNGOCONJUNCTIVAL FEVER Causes pharyngitis, which is often accompanied by conjunctivitis (pinkeye) and pharyngoconjunctival fever. Pharyngitis alone occurs in young children, particularly those younger than 3 years, and may mimic streptococcal infection. Patients have mild, flulike symptoms (including nasal congestion, cough, malaise, fever, myalgia, and headache).

ACUTE RESPIRATORY DISEASE A syndrome consisting of fever, cough, pharyngitis, and cervical adenitis. Usually caused by adenovirus serotypes 4 and 7. OTHER RESPIRATORY TRACT DISEASES: Coldlike symptoms, laryngitis, bronchiolitis. They can also cause a pertussis-like illness.

CONJUNCTIVITIS AND EPIDEMIC KERATOCONJUNCTIVITIS Cause a follicular conjunctivitis in which the mucosa of the palpebral conjunctiva becomes nodular Swimming pool conjunctivitis Irritation of the eye by a foreign body, dust , debris is a risk factor for the acquisition of this infection.

GASTROENTERITIS AND DIARRHEA Major cause of acute viral gastroenteritis; 15% of the cases of gastroenteritis in hospitalized patients. Serotypes 40 to 42 appear to be responsible for episodes of diarrhea in infants.

Laboratory Diagnosis Should be obtained from a site or secretion relevant to the disease symptoms. The presence of adenovirus in the throat of a patient with pharyngitis is usually diagnostic if laboratory findings eliminate other common causes of pharyngitis, such as Streptococcus pyogenes. Fluorescent antibody assays and the polymerase chain reaction can be used to detect, type, and group the virus. Serologic testing is rarely used except for epidemiologic purposes.

Cell cultures Cell cultures derived from epithelial cells (e.g., HeLa). Within 2 to 20 days, the virus causes a lytic infection with characteristic inclusion bodies. Such inclusions must be distinguished from those produced by cytomegalovirus.

Treatment, Prevention, and Control There is no approved treatment for adenovirus infection. Live oral vaccines have been used to prevent infections with adenovirus types 4 and 7 in military recruits.

Parvoviruses The smallest of the deoxyribonucleic acid (DNA) viruses. Only one member of the Parvoviridae, B19, is known to cause human disease.

B19 Causes erythema infectiosum, or fifth disease, a mild febrile exanthematous disease that occurs in children (it was the fifth of the childhood exanthems; the first four being varicella, rubella, roseola, and measles). Also responsible for episodes of aplastic crisis in patients with chronic hemolytic anemia and is associated with acute polyarthritis in adults. Intrauterine infection of a fetus may cause abortion.

Adeno-associated viruses (AAVs) Members of the genus Dependovirus in the family Parvoviridae. Commonly infect humans but replicate only in association with a second "helper" virus, usually an adenovirus.

Structure and Replication Small, a nonenveloped, icosahedral capsid. One linear, single-stranded DNA molecule Only one serotype of B19 is known to exist.

Pathogenesis and Immunity B19 targets and is cytolytic for erythroid precursor cells. Disease is determined by the direct killing of these cells and the subsequent immune response to the infection (rash and arthralgia).

First replicates in the nasopharynx or upper respiratory tract, then spreads by viremia to the bone marrow and elsewhere, where it replicates and kills erythroid precursor cells.

Pathogenesis and Immunity The initial febrile stage is the infectious stage. During this time, erythrocyte production is stopped for approximately 1 week as a result of the viral killing of erythroid precursor cells. A large viremia occurs and is accompanied by nonspecific flulike symptoms. Antibody stops the viremia and is important for resolution. The second, symptomatic stage is immune mediated. The rash and arthralgia seen in this stage coincide with the appearance of virus-specific antibody and the formation of immune complexes. Hosts with chronic hemolytic anemia (e.g., sickle cell anemia) are at risk for aplastic crisis.

The disease has a biphasic course.

Epidemiology Approximately 65% of the adult population have been infected with B19 by 40 years of age. Erythema infectiosum is most common in children and adolescents ages 4 to 15 years, who are a source of contagion. Arthralgia and arthritis are likely to occur in adults. Disease usually occurs in late winter and spring.

Clinical Syndromes: erythema infectiosum (fifth disease). Starts with a prodromal period of 7 to 10 days, during which the person is contagious: fever and nonspecific symptoms (sore throat, chills, malaise, and myalgia) as well as a slight decrease in hemoglobin levels. This period is followed by a distinctive rash on the cheeks, which appear as if they have been slapped.

Erythema infectiosum (fifth disease) A "slapped-cheek" appearance is typical of the rash for erythema infectiosum. The rash then usually spreads, especially to exposed skin such as the arms and legs, and then subsides over 1 to 2 weeks. Relapse of the rash is common.

Clinical Syndromes In adults causes polyarthritis. Arthritis of the hands, wrists, knees, and ankles predominates. Infection of immunocompromised people may result in chronic disease. The most serious complication: the aplastic crisis that occurs in patients with chronic hemolytic anemia (e.g., sickle cell anemia). The reduction results in a transient reticulocytopenia that lasts 7 to 10 days and a decrease in hemoglobin level.

Clinical Syndromes B19 infection of a seronegative mother increases the risk for fetal death. Infect the fetus and kill erythrocyte precursors, causing anemia and congestive heart failure (hydrops fetalis). Infection of seropositive pregnant women often has no adverse effect on the fetus. There is no evidence that B19 causes congenital abnormalities.

Laboratory Diagnosis Specific immunoglobulin M (IgM) or viral DNA must be detected (i.e., to distinguish the rash of B19 from that of rubella in a pregnant woman). Enzyme-linked immunosorbent assays for B19 IgM and IgG are available. The polymerase chain reaction test is a very sensitive method for detecting the B19 genome in clinical samples.

Treatment, Prevention, and Control No specific antiviral treatment or means of control is available. Vaccines are available for dog and cat parvoviruses.

Papovavirus family: Papillomaviruses and Polyomaviruses Papovavirus family (Papovaviridae) has been divided into two families, Papillomaviridae and Polyomaviridae. Are capable of causing lytic, chronic, latent, and transforming infections, depending on the host cell. Human papillomaviruses (HPVs) cause warts, and several genotypes are associated with human cancer (e.g., cervical carcinoma).

Papillomaviruses and Polyomaviruses BK and JC viruses, members of the Polyomaviridae, usually cause asymptomatic infection but are associated with renal disease and progressive multifocal leukoencephalopathy (PML), respectively, in immunosuppressed people. Simian virus 40 (SV40) is the prototype polyomavirus.

Structure and Replication Small, nonenveloped, icosahedral capsid viruses with double-stranded circular DNA genomes. They encode proteins that promote cell growth.

Human Papillomaviruses At least 100 types have been identified and classified into 16 (A through P) groups. HPV can be distinguished further as cutaneous HPV or mucosal HPV, on the basis of the susceptible tissue.

Structure and Replication The icosahedral capsid of HPV consists of two structural proteins forming 72 capsomeres. The HPV genome is circular and has approximately 8000 base pairs.

Computer reconstruction of cryoelectron micrographs of Human papillomavirus (HPV).

Progression of human papillomavirus infection Infect and replicate in the squamous epithelium of skin (warts) and mucous membranes (genital, oral papillomas) to induce epithelial proliferation.

PATHOGENESIS Are very tissue specific The wart develops as a result of virus stimulation of cell growth and thickening of the basal layer as well as the stratum granulosum. Koilocytes, characteristic of papillomavirus infection, are enlarged keratinocytes with clear haloes around shrunken nuclei.

PATHOGENESIS The viral infection remains local and generally regresses spontaneously but can recur. Innate and cell-mediated immunity are important for control and resolution of HPV infections.

The oncogenic potential of HPV Viral DNA is found in benign and malignant tumors, especially mucosal papillomas. HPV-16 and HPV-18 cause cervical papillomas and dysplasia, and at least 85% of cervical carcinomas contain integrated HPV-DNA. The E6 and E7 proteins of HPV-16 and HPV-18 have been identified as oncogenes because they bind and inactivate the cellular growth-suppressor (transformation-suppressor) proteins.

Harald zur Hausen Françoise Barré-Sinoussi Luc Montagnier

EPIDEMIOLOGY-HPV Resists inactivation and can be transmitted on fomites, such as the surfaces of bathroom floors, and towels. Is acquired (1) by direct contact through small breaks in the skin or mucosa, (2) during sexual intercourse, or (3) while an infant is passing through an infected birth canal.

EPIDEMIOLOGY Common, plantar, and flat warts are most common in children and young adults. Laryngeal papillomas occur in young children and middle-aged adults.

EPIDEMIOLOGY The most prevalent sexually transmitted infection in the world. Is present in 99.7% of all cervical cancers. HPV-16, HPV-18, HPV-31, and HPV-45 are high-risk types for cervical carcinoma, the second leading cause of cancer death in women. Approximately 10% of women infected with the high-risk HPV types will develop cervical dysplasia, a precancerous state. Multiple sexual partners, smoking, a family history of cervical cancer, and immunosuppresion are the major risk factors for infection and progression to cancer.

Progression of HPV-mediated cervical carcinoma Progression of HPV-mediated cervical carcinoma. HPV infects and replicates in the epithelial cells of the cervix, maturing and releasing virus as the epithelial cells progress through terminal differentiation. Growth stimulation of the basal cells produces a wart. In some cells, the circular genome integrates into host chromosomes. Expression of the other genes without virus production stimulates growth of the cells and possible progression to neoplasia

CLINICAL SYNDROMES: Warts Benign, self-limited proliferation of skin that regresses with time. HPV-1 through HPV-4, which infect keratinized surfaces, usually on the hands and feet.

Benign Head and Neck Tumors Benign epithelial tumors of the oral cavity. Laryngeal papillomas are commonly associated with HPV-6 and HPV-11 and are the most common benign epithelial tumors of the larynx. Can be life threatening in children because the papillomas may obstruct the airway.

Anogenital Warts Genital warts (condylomata acuminata) occur almost exclusively on the squamous epithelium of the external genitalia and perianal areas. Approximately 90% are caused by HPV-6 and HPV-11. Rarely become malignant in healthy people.

Cervical Dysplasia and Neoplasia HPV infection of the genital tract is a common sexually transmitted disease. Genital warts may appear like soft, sometimes cauliflower shaped. Cytologic changes indicating HPV infection (koilocytotic cells) are detected in Papanicolaou-stained cervical smears (Pap smears). Infection of the female genital tract by HPV types 16, 18, 31, and 45 is associated with intraepithelial cervical neoplasia and cancer. The first neoplastic changes noted on light microscopy are termed dysplasia. Approximately 40% to 70% of the mild dysplasias spontaneously regress.

LABORATORY DIAGNOSIS A wart can be confirmed on the basis of its characteristic histologic appearance, which consists of hyperplasia of the prickle cells and an excess production of keratin (hyperkeratosis). HPV infection promotes the outgrowth of the basal layer.

Papanicolaou-stained cervical smears (Pap smears) Detects the presence of koilocytotic (vacuolated cytoplasm) squamous epithelial cells, which are rounded and occur in clumps;

LABORATORY DIAGNOSIS DNA molecular probes and the polymerase chain reaction (PCR) from cervical swabs and tissue specimens are the methods of choice for establishing the diagnosis and typing of the HPV infection. Do not grow in cell cultures, and tests for HPV antibodies are rarely used except in research surveys.

TREATMENT, PREVENTION, AND CONTROL Warts spontaneously regress; are removed because of pain and discomfort, for cosmetic reasons, and to prevent spread to other people. They are removed through the use of surgical cryotherapy, electrocautery, or chemical means (e.g., 10% to 25% solution of podophilin), although recurrences are common.

A tetravalent HPV vaccine (Gardasil) consisting of the L1 major capsid protein Three immunizations for girls Starting at age 11 prior to sexual activity Bivalent HPV vaccine (Cervarix) HPV 16, 18 Three immunizations

Polyomaviridae The human polyomaviruses (BK and JC viruses) are ubiquitous but usually do not cause disease. They are difficult to grow in cell culture. SV40, a simian polyomavirus have been studied extensively as models of tumor-causing viruses but have not been associated with any human disease.

STRUCTURE AND REPLICATION Smaller, contain less nucleic acid and are less complex than the papillomaviruses. Enter the respiratory tract, after that The BK virus establishes latent infection in the kidney, and the JC virus establishes infection in the kidneys, in B cells, and in monocyte-lineage cells. Replication is blocked in immunocompetent persons.

PATHOGENESIS In immunocompromised patients, such as those with the acquired immune deficiency syndrome (AIDS), reactivation of the virus in the kidney leads to viral shedding in the urine and potentially severe urinary tract infections (BK virus) or viremia and central nervous system infection (JC virus).

EPIDEMIOLOGY Respiratory transmission is the probable mode of spread. Latent infections can be reactivated in people whose immune systems are suppressed as a result of AIDS, organ transplantation, or pregnancy. Approximately 10% of people with AIDS develop PML (progressive multifocal leukoencephalopathy), and the disease is fatal in approximately 90% of all cases.

CLINICAL SYNDROMES The BK and JC viruses are activated in immunocompromised patients, as indicated by the presence of virus in the urine of as many as 40% of these patients. Are also reactivated during pregnancy, but no effects on the fetus have been noted.

CLINICAL SYNDROMES The ureteral stenosis observed in renal transplant recipients appears to be associated with BK virus, as is the hemorrhagic cystitis observed in bone marrow transplant recipients. PML is a subacute demyelinating disease caused by the JC virus that occurs in immunocompromised patients, including those with AIDS.

LABORATORY DIAGNOSIS The diagnosis of PML is confirmed by the presence of PCR-amplified viral DNA in cerebrospinal fluid. Histologic examination of brain tissue obtained by biopsy or at autopsy will show foci of demyelination. The term leukoencephalopathy refers to the presence of lesions in only the white matter.

LABORATORY DIAGNOSIS Immunofluorescence, PCR analysis of cerebrospinal fluid, urine, or biopsy material for the particular genetic sequences can also be used to detect virus. Urine cytologic tests can reveal the presence of JC or BK virus infection by revealing the existence of enlarged cells with dense, basophilic intranuclear inclusions resembling those induced by cytomegalovirus. It is difficult to isolate BK and JC viruses in tissue cultures;

TREATMENT, PREVENTION, AND CONTROL No specific treatment for polyomavirus infection is available, other than to decrease the immunosuppression responsible for allowing the polyomavirus to be reactivated and symptoms to occur.