The DNA viruses that cause human diseases fall into the following two groups (Table 24.1); they are all double-stranded except for one:

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1 CHAPTER 24 Introduction to Viruses That Infect Humans: The DNA Viruses* *Lecture notes are to be used as a study guide only and do not represent the comprehensive information you will need to know for the exams Viruses in Human Infections and Diseases The DNA viruses that cause human diseases fall into the following two groups (Table 24.1); they are all double-stranded except for one: 1. Enveloped: Poxviruses, Herpesviruses, Hepadnaviruses 2. Naked (non-enveloped): Adenoviruses, Polyomaviruses, Papillomaviruses, and Parvoviruses (single-stranded DNA) See also Systems Profile 24.1 Pathogenic DNA Viruses Important Medical Considerations in Viral Diseases Target Cells Viruses have target cells based on the specific host cell receptors. Viruses can infect most types of human tissues, such as nervous tissue (polio) and the immune system (HIV). DNA viruses use the host cell nucleus of a eukaryote and RNA viruses use the cytoplasm to replicate in each cell location. Visible changes the viruses have on the host cell is called the cytopathic effect. A lytic virus will kill the host cell, leading to further damage. Scope of Infections Viruses can range from self-limiting, like the common cold, to life threatening, like HIV. The viral infection starts with a portal of entry, progresses through the stages of disease all the while causing manifestations of the diseases such as rashes, fevers and swollen glands. Protection from viral infections are done by the host immune system and administering vaccines. Viral Persistence, Latency, and Oncogenicity - When viruses establish a long term infection with the host, this is termed a persistent infection, which can last for many years to life (fig. 24.1). Two types of persistent infections are chronic infections where the virus multiplies at a slow rate, and LATENT INFECTIONS the virus enters a dormant phase. Some persistent viruses are oncogenic, which means they can cause cancer. See list on page 737. Congenital and Perinatal Transmission some viruses can cross the placenta from infected mother to embryo / fetus. Infection of the fetus can cause birth defects that are present at birth called congenital birth defects. Viruses that are teratogenic can cause these types of birth defects. Viral Diagnosis Done by a variety of methods such as clinical signs and symptoms, and lab methods. Review figure for a summary of methods. Overview of DNA Viruses Viruses can be classified based on their viral composition and structure. Family names and viral types are used to classify viruses. For the purposes of this book, such an extensive classification system will not be used. For the purposes of this book DNA viruses that cause human disease are placed into six groups (see Table 24.1) Enveloped DNA Viruses: Poxviruses Many of these are dermotropic viruses: they have clinical manifestations affecting the skin. They may enter the host through the skin, but others may enter through the respiratory tract or alimentary tract. Classification and Structure of Poxviruses 1

2 Poxvirus, the etiologic agent of smallpox, is enveloped and has complex cylindrical capsids with complex coats. (Fig 24.2). It is characterized by the development of skin eruptions that eventually form a crust (fig. 24.3). When the crust falls off, it leaves scars called "pockmarks", or pox. Severe forms of the disease are fatal to 15-45% of those infected. Two varieties of poxvirus are vaccinia and variola. Variola major is a highly virulent strain. Infection with variola major leads to toxemia, shock, and intravascular coagulation. Vaccinia forms are used to create the smallpox vaccine. Smallpox: A perspective Transmission: usually person-to-person in aerosols. Fomites may also be a source. In the late 1700's, Edward Jenner experimented with a cowpox "germ." It provided persons with protection to smallpox. He would take the pus from lesions of persons infected with cowpox and inoculate susceptible individuals. The term vaccination is thus derived from the Latin word vacca, meaning cow. The vaccination protects up to 10 years. The small pox virus only lives in humans. Through efforts by the World Health Organization, a disease that has plagued human beings since antiquity was declared "eradicated" October 26, Stocks of smallpox still exist in (hopefully) very secure labs in the US, Russia, and even, perhaps, elsewhere. DISEASE MANIFESTATIONS Exposure to smallpox usually occurs through inhalation of droplets or skin crusts. A rash will begin in the pharynx, then spread to the face and extremities. People who survive any form of smallpox nearly always developed life-long immunity. SMALLPOX VACCINATION The vaccine uses a vaccinia virus punched into the skin. A red pustule will form (fig. 24.4). The vaccine provides long term protection. Small pox vaccine has been discontinued for most populations. Other Poxvirus Diseases A sexually transmitted molluscipoxvirus causes a disease called molluscum contagiosum characterized by small, waxy papules at the site of skin eruption. A possible emerging disease in Africa is monkeypox, which is believed to have jumped from monkeys to humans since the cessation of smallpox vaccination; several cases appeared in the mid-west U.S. (prairie dogs were infected by imported Gambian rats). For these reasons, and due to concerns of bioterrorism, vaccination is being reintroduced. See CDC 1 recommendations for smallpox vaccination. Cowpox is a rare human disease confined to the skin of the hands. It is usually acquired from coming into contact with infected udders and teats of cows Enveloped DNA Viruses: The Herpesviruses Herpes Simplex infections are caused by an enveloped, icosahedral capsid, dsdna virus whose members include (fig. 24.5): herpes simplex 1 and 2 (HSV), varicella-zoster (VZN), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). They can cause fever blisters, genital herpes, chickenpox & shingles, mononucleosis, and salivary infections respectively. Viral infections may involve skin, eye, mucous membranes, and the nervous system. The infection is usually acquired by direct contact through broken skin or mucous membranes. See list page 739. Herpes simplex can lay dormant in the ganglia of sensory neurons for years (fig and fig ). General Properties of Herpes Simplex Viruses Herpes Simplex Virus I (HSV-I) is typically associated with the mouth and lips causing: gingivostomatitis, small blisters of the oral mucosa, and cold sores (fever blisters) on the lips. Herpes Simplex Virus II (HSV-II) is a genital infection although HSV-I has been found to cause genital infections also. Humans appear to be the only natural reservoir for herpes simplex virus. See Table Epidemiology of Herpes Simplex 1 2

3 The herpes simplex viruses are sensitive to the environment, therefore transmission is usually limited to direct exposure to secretions containing the virus. Herpes simplex can be transmitted with and without active lesions. Infection tends to be age specific HSV-1 is usually contracted in infancy and early childhood; HSV-2 infection tends to occur between the ages of 14 and 29. The Nature of Latency and Recurrent Attacks Most primary infections of herpes simplex viruses multiply in the distal regions of sensory neurons and are carried to the ganglia. HSV-I lies dormant in the trigeminal (5 th ) cranial nerve, which innervates the oral region. HSV-2 lies dormant in ganglion of lumbosacral spinal nerve trunk. They reappear periodically. A tingling or burning sensation may precede eruption of the skin. It can be triggered by stress, ultraviolet irradiation, or after a febrile (fever) disease. The lesions are initially blister-like before they rupture and develop a scab. See Table 24.2 for a comparison of Type 1 and Type 2 HSV. Type 1 Herpes Simplex in Children and Adults Herpes labialis, also known as fever blisters or cold sores, is the most recurrent HSV-1 infection. Blisters crop up on the skin of the lips (fig. 24.7a). HSV-1 is the causative agent of gingivostomatitis (fig. 24.7b), which is an inflammation of the oral mucosa gums, tongue, soft palate and lips. In adolescents it can occur as pharyngitis, marked by a sore throat, fever, swollen lymph nodes and difficulty swallowing. Herpetic keratitis, also called ocular herpes, is an infection of the eye where the virus travels to the ophthalmic rather than the mandibular branch of the trigeminal nerve. In some cases it is introduced to the eye by contaminated fingers or contact lenses. Type 2 Herpes Infections HSV-2 infections usually occur when a person reaches sexual maturity. Genital herpes (herpes genitalis) is a sexually transmitted disease (STD) characterized by blisters on the skin and mucous membranes of the genitourinary tract (fig. 24.8). The blisters ulcerate after 4-5 days. The outbreak may be accompanied by fever, exhaustion, malaise, and anorexia. The lesions can reoccur and the virus can remain dormant in nerve cells during latent periods. Individuals are infected for life and there appears to be an increase of cervical cancer among women with herpes. The disease is transmitted when the blisters and ulcers are present, although one should assume it is transmissible at all times. Herpes of the Newborn The fetus can be infected by circulating viral particles during development, leading to severe damage of the fetus or stillbirth. See fig for an example of neonatal herpes simplex. It is more common that the virus is transmitted to the baby during delivery (especially during an outbreak). Cesarean sections to protect the infant are often performed. Because of the lack of a fully functional immune system in infants, exposure to the disease can be severe or fatal. Miscellaneous Herpes Infections A hazard for health care workers who handle patients or their secretions without hand protection is a disease called whitlow (fig ). Those who work in gynecology, obstetrics, dentistry and respiratory therapy are at risk. Life Threatening Complications HSV-1, in rare cases, can cause herpes simplex encephalitis. The virus moves along the nerve pathways to the brain or spinal cord. Persons who have underlying immunodeficiency are more prone, such as AIDS and cancer patients. 3

4 Diagnosis, Treatment, and Control of Herpes Simplex Look for signs and symptoms such as painful vesicles on the mucous membranes of the mouth or genitalia. Lab tests like Pap smear are done (fig ). Prevention: avoid sexual contact with infected individuals during the time period when blisters are developing or ulcers are present. However, there isn t necessarily any guarantee that the virus will not be transmitted between partners even if one doesn t have blisters. Treatment: Acyclovir (Zovirax ) is a synthetic purine analog used to inhibit replication of the virus. It is available in topical, oral, and intravenous forms. The drug does not eliminate the virus. Valcyclovir (Valtrex ) reduces the incidence of recurrences and the duration and severity of episodes. Intravenous acyclovir is even more effective than oral, but there are greater side effects (nephrotoxicity). Again, nothing kills the virus. Tracking STDs: See also Pathogen Profile #1 Herpes simplex virus 1 and 2 (HSV-1. HSV-2) The Biology of Varicella-Zoster Virus Varicella-Zoster virus infections: chickenpox and shingles. The same virus has two forms of the disease, it is known by its composite name, varicella-zoster virus (VZV) (fig ). Epidemiological Patterns of VZV Infection Humans are the only natural host for the varicella-zoster virus. It is harbored in the respiratory tract, but it is communicable from both respiratory droplets and the fluid of active skin lesions. Varicella (Chickenpox) Chickenpox 2 is a mild infection, with a rash lasting 5-10 days in children (fig a). About 14 days after infection, a papular rash appears on the skin and mucous membranes. They soon fill with a watery fluid, encrust, then drop off (or are scratched off since they itch); occasionally scarring results. Initial symptoms include fever, headache, and malaise. The disease is more severe in adults and can lead to pneumonia (secondary bacterial infection) with 15% mortality. Herpes Zoster (Shingles) Chickenpox may reappear as shingles in adults because the virus lies dormant in nerve ganglia (Fig b and 24.12c). When reactivated, it moves along axons to the skin innervated by those sensory neurons. Lesions similar to chickenpox occurs. It is painful both on the skin and along the nerves. A vaccine is now available and required in many states. See the CDC 3 for detail on side effects. 2 Note: Chickenpox isn t caused by a poxvirus, but a herpes virus and does not occur in chickens

5 Diagnosis, Treatment, and Control of VZV Infection Cutaneous manifestations of varicella and shingles are sufficiently characteristics for readily clinical recognition. Look for skin lesions and multinucleate giant cells in stained smears from vesicle scrapings. The Cytomegalovirus Group The cytomegalovirus group (CMV) is named for their tendency to produce giant cells with nuclear and cytoplasmic inclusions (fig ). The CMV, also termed salivary gland virus, is the most ubiquitous pathogens of humans. Epidemiology of CMV Disease Human populations have been tested for the presence of the virus based on antibodies. About 50% of women of childbearing age test positive for the virus, and 10% of newborns have been shown to be infected. CMV is the most prevalent fetal infection. CMV is transmitted by body fluids such as saliva, respiratory mucous, milk, urine, semen and cervical secretions. Transmission usually involves intimate exposure, such as sexual contact, vaginal birth, and transplacental. CMV is carried in a latent state in white blood cells, such as monocytes. Infection and Disease Most healthy adults and children are asymptomatic with a primary CMV infection. Three groups can develop a more serious form of the disease: fetuses, newborns and immunodeficient adults. Congenital CMV is seen in about 20% of pregnancies. Newborns can have enlarged livers and spleen, jaundice and ocular inflammation. More severe cases can cause death. Newborns who do survive a severe infection develop long term neurological disorders. CMV mononucleosis is a syndrome that is similar in disease characteristics to Epstein-Barr virus. CMV mononucleosis is typical in adults, but it can be seen in children. CMV mononucleosis can also be prevalent in AIDS patients and those receiving a kidney transplant. Diagnosis, Treatment, and Prevention of CMV Infection In infants, CMV infection must be differentiated from toxoplasmosis, rubella, and herpes simplex. In adults it must be distinguished from EBV and herpes simplex. CMV can be isolated from a variety of organs and epithelial tissue. CMV can be detected by using monoclonal antibodies and PCR. Drug therapy is reserved for immunesuppressed patients, such as ganciclovir. Epstein-Barr Virus Mononucleosis or infectious mononucleosis is caused by Epstein-Barr virus, a type of Herpes virus that infects the lymphatic system. Early symptoms of the disease include exhaustion and a general poor feeling. The disease is characterized by extreme exhaustion, fever, sore throat (fig ), pharyngitis, tonsillitis, swollen lymph nodes, and swollen spleen. EBV has genes that transforms certain lymphocytes into malignant cells. Epidemiology of Epstein-Barr Virus Has a preference for human lymphoid tissue and salivary glands. Modes of transmission are by direct contact through oral contact and contamination with saliva. The nature of infection depends on the person s age socioeconomic level, geographic region and genetics. In less well developed regions, such as Africa, the rates of transmission are higher. 5

6 In industrialized nations, exposure to EBV is usually postponed until adolescence or early adulthood. EBV is prevalent in college-age adults, also called the kissing disease or mono. There is some evidence that there is a connection between EBV and multiple sclerosis. Recovery is 4-8 weeks with continued bouts of exhaustion. Poor sanitation areas have a higher rate of infections (80-95% of those under 2 years old), but a low incidence of the disease. Industrialized areas with good sanitation have a lower infection rate (25% of those under 2 and 50% of those under 20). Of the 50% infected, 50% develop the signs and symptoms of the disease. Diseases of EBV The epithelium of the oropharynx is the portal of entry for EBV. The virus moves to the parotid gland, the takes residence in B cells. In some people the course of infection and latency is asymptomatic. The symptoms are sore throat, high fever and lymphadenopathy. A notable sign of mononucleosis is sudden leukocytosis, consisting mainly of B cells. Tumors and Other Complications Associated with EBV Ruptured spleen, Guillain-Barre 4 syndrome and hemolytic anemia. Epstein-Barr virus may also be responsible for two types of cancer: African Burkitt's lymphoma (fig ) and nasopharyngeal carcinoma. Any person with an immune deficiency is highly susceptible to EBV. Also associated with AIDS-related lymphomas. Diagnosis, Treatment and Prevention of EBV Infection Lab diagnosis is necessary, such as a differential blood count showing lymphocytosis and large atypical lymphocytes (Fig ). Serological analysis is also done. In more severe cases acyclovir is given. See also Pathogen Profile #3 Epstein-Barr Virus (EBV) Diseases of Herpesviruses 6, 7, and 8 Human herpesvirus 6 (HHV-6) is the causative agent of human B-lymphotropic virus. It is the cause of roseola, also known as roseola infantum, that affects babies between 2 and 12 months of age (fig ). Infected adults have mononucleosis like symptoms. HHV-6 has been linked to a number of carcinomas and multiple sclerosis. HHV-7 is related to HHV-6, and can cause similar diseases. Karposi s sarcoma, a tumor of AIDS patients, is caused by HHV The Viral Agents of Hepatitis Hepatitis is an inflammation of the liver, manifested as anorexia (weight loss), jaundice (yellow-green color change of skin), enlargement of the liver, and fever (fig ). The three major viruses (some DNA, some RNA) that can cause hepatitis are: hepatitis A virus (HAV). Hepatitis A or HAV is an infectious hepatitis acquired by the fecal-oral route. It is an icosahedral capsid, +ssrna virus. Incubation period = 2-7 weeks. Symptoms = fever, gastrointestinal tract disorder, mild jaundice, occasional liver 4 Guillain-Barre syndrome is a complication following some viral infections. It is a reversible paralysis. 6

7 impairment (rare cases can be fatal). Onset is acute and duration of the disease is short. Hepatitis B (HBV); non A, non B hepatitis, also called hepatitis C (HCV). Non A, non B hepatitis or hepatitis C (HCV) is caused by an enveloped +ssrna retrovirus. Transmission is from contaminated blood, serum and intimate contact (sexually transmitted). Incubation period = 2-8 weeks. Symptoms = fever, rash, arthritis. Onset of the disease is acute to chronic. Complications include chronic inflammation and cirrhosis of the liver. Liver transplants are not always successful due to easy reinfection during surgery. Fatal if untreated. Symptoms = fever, rash, arthritis. Onset of the disease is acute to chronic. Complications include chronic inflammation and cirrhosis of the liver. Liver transplants are not always successful due to easy reinfection during surgery. Fatal if untreated. There is no vaccine for HCV, but there are vaccines against HAV and HBV. Also note: Hepatitis D and hepatitis E are rare and/or still emerging. Hepatitis D Hepatitis D virus (HDV) is an incomplete RNA virus. It requires Hepatitis B antigens and can therefore only be acquired as a coinfection with HBV. It is diagnosed by the presence of anti-hdv antibodies in the blood. Intravenous drug users are at greatest risk. Chronic HDV infection is associated with a poorer prognosis than uncomplicated chronic HBV infection, with more rapid progression of cirrhosis. Death often occurs within 2-5 years. Treatment is unsatisfactory. Interferon- has a marginal effect in slowing progression of the disease. Liver transplants are often the only option, but carry with it a 15 to 20% risk that infection of the transplanted liver with both HDV and HBV will cause death from hepatitis. The 1-year survival rate of patients with transplants for cirrhosis due to chronic HDV infection is about 50%. Hepatitis E Hepatitis E virus (HEV) is incompletely characterized. It has been responsible for several epidemics in the Middle East and parts of Asia. The source has been contaminated water supplies. In epidemics, the source can usually be traced to contaminated food or water, although direct spread can occur. The best treatment is prevention. Hepatitis B Virus and Disease Hepatitis B or HBV causes serum hepatitis (large viral load in the blood). A blood analysis of an infected person shows the Dane particle (fig ) Epidemiology of Hepatitis B HBV is a chronic infection of the liver, which then enters the blood. It has been isolated from semen and vaginal secretions. It can be acquired by blood transfusions contaminated syringes or instruments, or via the fecal-oral route. Hepatitis B is an enveloped icosahedral dsdna hepadnavirus. Incubations period = 1-6 months. Newborns can be infected during birth. Pathogenesis of Hepatitis B virus HBV enters by a break in the skin, mucous membranes or injection into the blood stream. Eventually it reaches the hepatocytes of the liver. Symptoms = fever, rash, arthritis (fig ). Onset is gradual and duration of the disease is chronic. Complications include chronic active hepatitis and liver cancer, hepatocellular carcinoma. 7

8 Diagnosis and Management of Hepatitis B Infection Risk factors are used to diagnose HBV and HAV. Drug abuse and increased exposure during sex are the common risk factors. HBV can cross the placenta. HBV is tested as part of the STORCH test. Chronic infection is managed by interferon. Passive immunization with the HBIG vaccine is done Nonenveloped DNA Viruses 1. ADENOVIRUSES FYI ONLY!!! Adenoviruses are common infectious agents of lymphoid tissue, the respiratory tract, and eyes. Transmission is via close contact with secretions. Pathologies include: common cold with fever and rash keratoconjunctivitis a severe eye infection cystitis an acute urinary infection Genetically altered forms of adenovirus are being explored as vectors for gene therapy. Papillomavirus Epidemiology and Pathology of the Human Papillomaviruses Human papillomaviruses (HPVs) - Etiologic agent of skin tumors called papillomas, verrucas, or warts. Transmission is by close contact with infected skin or fomites. Common warts are rough, painless lesions on hands; plantar warts are more painful, flat, benign tumors on the feet and trunk (fig a). Wearing sandals in public showers can reduce transmittance. Genital warts are verrucas that start as tiny bumps on membranes or genital skin (fig b). Common STD. According to the CDC 5 : approximately 20 million people are currently infected with HPV. At least 50 percent of sexually active men and women acquire genital HPV infection at some point in their lives. By age 50, at least 80 percent of women will have acquired genital HPV infection. About 5.5 million Americans get a new genital HPV infection each year. Data suggest that infections with HPV16 and HPV18 lead to an increased risk of cervical cancer. A vaccine against HPV16 has recently been approved for use by the FDA and is now available. It is hoped that one day, widespread use of the vaccine will almost eliminate this type of cancer (fig ). Diagnosis, Treatment, and Prevention of HPV Infection Strategies for all types of warts include direct chemical application of podophyllin and physical removal of affected areas by cauterization, freezing (with liquid nitrogen), or laser surgery. While interferon therapy is effective in some cases warts may recur 5 8

9 because treatments rarely destroy all viral particles. Two effective HPV vaccines are Gardasil and Cervarix. Immunization with the HPV vaccine is recommended for both males and females prior to becoming sexually active. 9