Chapter VI.1. Virology
Mary Rose Nino
February 2015

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Loren G. Yamamoto. This current second edition chapter is a revision and update of the original authorís work.


A 5-year-old boy presents to the clinic with the chief complaint of fever and body aches for two weeks. His temperature at home was 39 degrees C (102.2 degrees F). He was given acetaminophen, resulting in normalization of his temperature and relief of his body aches. His oral liquid intake has remained good and he has not had any vomiting. His associated symptoms include a slight cough and nasal congestion, but no sore throat, headache, diarrhea, abdominal pain, or urinary complaints.

Exam: T37.2, P80, R25, BP 90/60, oxygen saturation 100% in room air. Height and weight are at the 50th percentile. He is alert, active, and cooperative. He is not toxic and not irritable. Physical exam findings are unremarkable except for nasal congestion.

You explain to his mother that he has a nonspecific "flu-like illness" caused by a virus. She tells you, "That's what he had two weeks ago. How can he keep getting the same virus over and over again? What's the name of this virus anyway and how can he get rid of it?" You explain that this is not the same virus because his immune system eventually rids the body of the virus. However, there are many different types of other viruses of which he is susceptible. While you are uncertain about the specific viral agent causing his illness, you realize there are no antiviral treatments against this virus.


Although most clinicians have a basic background of bacteriology, their knowledge of virology is usually more limited. The ability to differentiate between the various classes of bacteria is essential in selecting appropriate antibiotics. However, since we have only a handful of antiviral agents, it is often unnecessary (from a therapeutic decision standpoint) to identify the infectious viral agent. Nevertheless, as more antiviral agents become available, it is necessary for clinicians to improve their knowledge of virology, especially the medically important viruses, for their optimal use in the future.

Viruses are tiny, obligate, intracellular organisms (ranging from about 20 to 300 nm in diameter) that utilize the host cell machinery in order to replicate and produce hundreds of viral progeny within the cell. They are relatively inactive outside of living cells. While too small to visualize under a light microscope, the "cytopathic effect" (morphological changes) of viruses on eukaryotic cells in a cell culture media is visible by light microscopy. Thus, the only way that viruses can be grown in a lab is in cell culture media. Other clinical laboratory methods utilized to identify the presence of viruses are: immunologic assays, antibody serology, polymerase chain reaction (PCR) to detect nucleic acid, detection of reverse transcriptase and electron microscopy.

Whereas bacteria are classified based on their response to gram staining, the basis for the classification of viruses is the presence or lack of an envelope outside of the nucleocapsid and the type of nucleic acid (DNA or RNA, but not both) in their genome. Viruses are either naked, with an icosahedral head shape, or enveloped. The envelope is created by the host cellís membrane budding off. Non-enveloped viruses can also be called nucleocapsid viruses. In general, there are four types of disease patterns produced by viruses:

Acute infection: Death of the host cell as viral particles are released; caused by both naked and enveloped viruses.

Chronic infection: Continued release of viral particles for a period of 6 months or more; caused only by enveloped viruses, such as hepatitis B and HIV (human immunodeficiency virus)

Latent infection: Viral nucleic acid sequence is incorporated into the host cell, but the host cell is not actively producing viral particles unless it is reactivated in the future; caused by viruses such as Herpes simplex, which is characterized by recurrent episodes of clinical infection.

Post-infectious or para-infectious phenomena: Result of the body's immune system damaging the host cells and tissues in an effort to get rid of the virus; most clinically evident in encephalitis and myocarditis.

The genomes of viruses can consist of: 1) single-stranded or double-stranded DNA, 2) single-stranded positive-strand RNA (or sense RNA), 3) single-stranded negative-strand RNA (or antisense RNA), or 4) double stranded RNA that is covered by a protein coat called a nucleocapsid. DNA viruses usually contain double stranded DNA (dsDNA), which undergoes separation and replication to form new dsDNA for the newly formed viral particles. Other DNA viruses utilize single stranded DNA (ssDNA). For RNA viruses, a positive-strand RNA genome consists of a single-stranded RNA (ssRNA) that functions as viral messenger RNA (mRNA) in the synthesis viral proteins using the hostís ribosomes. A negative-strand RNA genome must first be transcribed to viral mRNA by viral RNA polymerase before using the hostís ribosomes to synthesize viral proteins. Retroviral RNA viruses, which fall under the category of positive-strand RNA viruses, contain a single strand of RNA and an enzyme called reverse transcriptase that is able to synthesize dsDNA from the RNA strand, which is then integrated into the host cell genome. There are a few exceptions to these general classes.

DNA VIRUSES

DNA viruses include parvoviruses, papovaviruses, adenoviruses, hepadnaviruses, herpesviruses, and poxviruses, which can be remembered by "Poor Pappy Adds Hep to Her Pox." The first three are naked DNA viruses and the latter three are enveloped DNA viruses.

Parvoviruses most commonly cause veterinary disease; however, human hosts can be infected with human parvovirus B19, the virus responsible for Fifth disease (erythema infectiosum), a childhood viral exanthem. Clinical manifestations of Fifth disease include pink cheeks ("slapped cheeks"), fever, and a slight rash to the body. Human parvovirus infection is more severe in children and adults with hemoglobinopathies (thalassemia, sickle cell disease, etc.) and is responsible for aplastic crisis in sickle cell disease. It can cause mild anemia in healthy individuals, but results in severe erythrocyte suppression in patients with hemoglobinopathies. A fetus with thalassemia may be stillborn due to hydrops fetalis if the mother is infected by human parvovirus B19 during her pregnancy.

Papovaviruses include human papillomaviruses (HPV) and polyomaviruses. Papillomaviruses cause various types of cervical cancer and papillomas of the skin and mucous membranes, such as plantar warts and genital warts (condyloma acuminata). There is now an HPV vaccine that is protective against HPV-6,11,16 and 18. HPV-18 accounts for about 70% of all cervical cancers, while HPV-6 and 11 cause about 90% of genital warts. Polyomaviruses mostly affect birds, but they also include the JC virus (which causes progressive multifocal leukoencephalopathy dementia in immunocompromised patients) and the BK virus (which causes kidney disease in immunocompromised patients). Adenoviruses commonly affect children and are responsible for infections of the upper and lower respiratory tracts and are primarily self-limited. The different types of adenoviruses are classified by serotype numbers and can cause combinations of fever, conjunctivitis, pharyngitis, rhinitis, and pneumonia. Some adenoviruses cause gastroenteritis. Hepadnaviruses include hepatitis B virus, which is the most important virus in the family. Hepatitis B virus is an enveloped virus making it capable of chronic disease in some hosts. Chronic hepatitis B may cause chronic hepatitis, hepatic failure and hepatocellular carcinoma (most common cancer worldwide).

Herpesviruses include herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 8 (HHV8) and are known for their ability to cause latent infections. HSV and VZV are similar in that they both begin with acute infection followed by latent lifelong infection and periodic reactivation of symptomatic infection. The virus resides in nerve tissue and upon periodic reactivation, mucosal or vesicular lesions may recur. HSV-1 causes recurrent oral herpes while HSV-2 causes recurrent genital herpes. Both cause initial acute infections with fever, viremia, mucosal lesions and/or central nervous system infection. HSV-1 usually causes an initial acute infection characterized by gingivostomatitis (high fever, gum swelling and multiple mouth sores on the lips and anterior tongue). Similarly, VZV causes an acute systemic infection manifested as varicella (or chickenpox), with subsequent reactivation of latent infection manifested as zoster (or shingles).

EBV and CMV are similar in that they both cause syndromes of prolonged viral infection with fever, malaise, lymphadenopathy, and organomegaly. EBV syndrome is also known as infectious mononucleosis and also includes tonsillitis. EBV is capable of latent infection and is associated with Burkitt's lymphoma (the cells of which contain EBV DNA). HHV8 causes Kaposiís sarcoma, a tumor that may occur in immunocomprised or immunocompetent hosts.

CMV and HSV cause recognizable congenital viral syndromes when a pregnant mother develops an initial acute infection during early pregnancy. The acute infection results in viremia, which may infect the fetus and placenta resulting in a recognizable pattern of findings including: central nervous system calcification, microcephaly, thrombocytopenia, petechial rash, small for gestational age, etc. Reactivated maternal infection does not usually result in a systemic viremia, so congenital infection is not likely associated with anything other than an acute maternal infection. Congenital infection should be distinguished from perinatal infection in that congenital infection occurs during early gestation while perinatal infection occurs at the time of birth or just after. For example, a mother with a history of genital herpes many years ago is at no risk for delivering an infant with congenital herpes, but the infant is still risk for perinatal herpes, which may present as an acute encephalitis or overwhelming acute viremia. Neonates are especially prone to encephalitis with HSV-1 and HSV-2. Specific measures must be taken to prevent HSV exposure to neonates, including Cesarean sections in mothers with a history of genital herpes, prior to the rupture of membranes, to prevent neonatal exposure to occult genital herpes lesions.

Poxviruses include variola virus (smallpox), vaccinia (cowpox) and molluscum contagiosum virus, but do not include VZV (chickenpox), which is in the herpesvirus family. Smallpox, which has been eradicated except in bio-warfare programs, is a highly contagious virus with a high mortality rate. Vaccinia virus is called cowpox because of its discovering in dairy cattle. Milkmaids would get a mild infection with vaccinia, manifested as pox lesions on their milking hands. Vaccinia virus infection elicits cross-immunity against smallpox. The classic observation that milkmaids never got smallpox was noticed by Edward Jenner who eventually demonstrated that inoculation with vaccinia virus could prevent smallpox (variola virus infection), a process later termed vaccination. In the United States, molloscum contagiosum virus is the only member of the family Poxviridae that causes disease in humans.

RNA VIRUSES

Positive-strand viruses include picornaviruses, caliciviruses, flaviviruses, togaviruses, coronaviruses, and retroviruses, and can be remembered by "Pete Can Float Toward the Coast Backward (retrovirus = backward in the mnemonic)."

Picornaviruses include poliovirus, enterovirus, echovirus, coxsackievirus, rhinovirus and hepatitis A virus (HAV), which can be remembered by ďPEECoRnA.Ē Polio is covered in a separate chapter, but is rarely found in the United States since the advent of the polio vaccine. Enteroviruses are transmitted via the fecal-oral route and cause viral meningitis, occasional encephalitis, gastroenteritis and myocarditis. Coxsackie viruses usually cause fever and stomatitis, such as in herpangina and hand-foot-mouth disease; however Coxsackie B19 can cause myocarditis as well. Echoviruses cause fever, rash, and aseptic meningitis. Rhinoviruses cause common cold symptoms and bronchiolitis in young infants. Hepatitis A virus is an enterovirus that primarily affects children and is acquired by fecal-oral transmission.

Caliciviruses include Norwalk virus, which causes gastroenteritis (especially in adults), and hepatitis E virus (HEV). HEV is also transmitted by fecal-oral route similar to HAV. Flaviviruses include hepatitis C, yellow fever, dengue fever and St. Louis encephalitis. Hepatitis C virus is the predominant type of viral hepatitis in the United States, predisposing infected individuals to chronic hepatitis and hepatic carcinoma. Togaviruses include the equine encephalitis viruses, such as western equine encephalitis and eastern equine encephalitis, and rubella virus (German measles). Coronaviruses include multiple serotypes, which cause cold symptoms.

Retroviruses include human immunodeficiency virus (HIV), which can progress to acquired immunodeficiency syndrome (AIDS), and human T-cell lymphotrophic virus, which can cause tropical spastic paraparesis, an autoimmune disorder.

Negative-strand RNA viruses include rhabdoviruses, filoviruses, paramyxoviruses, arenaviruses, orthomyxoviruses and bunyaviruses, and can be remembered by "Raspberry Filled Parfaits Are Often Burned." The rabies virus is the most important of the rhabdoviruses. Infection follows after the bite of a wild animal (e.g., skunks, foxes, raccoons, bats) leading to fatal encephalitis. Ebola virus is the most important of the filoviruses. Rabies and Ebola viruses cause deadly viral infections. Paramyxoviruses include rubeola (measles), mumps, respiratory syncytial virus (RSV), and parainfluenza virus (colds, laryngitis, croup). The routine vaccination against measles, mumps, and rubella viruses has decreased the incidence of these infections in the United States and is important since congenital malformations can result in pregnant women infected with the rubella virus. Premature and other high-risk infants routinely receive passive immunity against RSV. Arenaviruses include lymphocytic choriomeningitis virus and Lassa fever virus. Orthomyxoviruses include influenza A (primary cause of recurrent flu epidemics) and B. Hanta virus is the most important bunyavirus and is also a deadly viral infection.

Double-stranded RNA viruses include orbiviruses, rotaviruses, and reoviruses (ORR). Orbiviruses include Colorado tick fever virus. Rotaviruses are a major cause of pediatric diarrhea; however, there exists a vaccination against rotavirus. Reoviruses cause febrile illnesses without other specific findings.

Summary of virus classifications
I. DNA viruses (Poor Pappy Adds Hep to Her Pox)
. . . A. Naked
. . . . . 1. Parvovirus (human parvovirus B19)
. . . . . 2. Papovavirus (papillomavirus, polyomavirus)
. . . . . 3. Adenovirus (many which cause febrile respiratory infections)
. . . B. Enveloped
. . . . . 1. Hepadnavirus (hepatitis B)
. . . . . 2. Herpesvirus (HSV, VZV, EBV, CMV, HHV8)
. . . . . 3. Poxvirus (variola, vaccinia, molluscum contagiosum)
II. Positive-strand RNA viruses (Pete Can Float Toward the Coast Backward)
. . . A. Naked
. . . . . 1. Picornavirus (PEECoRnA = polio, entero, echo, coxsackie, rhino, hepA)
. . . . . 2. Calicivirus (Norwalk, hepatitis E)
. . . B. Enveloped
. . . . . 1. Flavivirus (yellow fever, dengue, St. Louis encephalitis, hepatitis C)
. . . . . 2. Togavirus (rubella, equine encephalitis)
. . . . . 3. Coronavirus (colds)
. . . . . 4. Retrovirus (HIV)
III. Negative-strand RNA viruses (Raspberry Filled Parfaits Are Often Burned)
. . . A. Naked - none
. . . B. Enveloped
. . . . . 1. Rhabdovirus (rabies)
. . . . . 2. Filovirus (Ebola)
. . . . . 3. Paramyxovirus (measles, mumps, RSV, parainfluenza)
. . . . . 4. Arenavirus
. . . . . 5. Orthomyxovirus (influenza)
. . . . . 6. Bunyavirus (Hanta)
IV. Double-stranded RNA viruses (ORR)
. . . A. Orbivirus (Colorado tick fever)
. . . B. Rotavirus
. . . C. Reovirus


Questions

1. Name the 3 naked and 3 enveloped viruses in the DNA virus families.

2. Based on duration of infection, how do naked viruses differ from enveloped viruses?

3. Name 6 viruses that belong in the family Picornaviridae.

4. How are viruses that belong to the family Herpesviridae similar?

5. Name 4 viruses that can cause cold symptoms.

6. Name the families of viruses that have positive-strand RNA.

7. Name two naked (non-enveloped) viruses that cause chronic infection.

8. Name the families of viruses that have negative-strand RNA.

9. Naked viruses are mostly of what morphologic shape on light microscopy?

10. Name 4 families of viruses that cause central nervous system infections.


References

Hawley LB. High-Yield Microbiology and Infectious Diseases. 2000, Philadelphia: Lippincott Williams & Wilkins.

Levinson W. Part IV. Clinical Virology. In: Levinson W, ed. Review of Medical Microbiology & Immunology. 12th ed. New York: McGraw-Hill; 2012.


Answers to questions

1. Poor Pappy Adds Hep to Her Pox: Parvovirus, papovavirus, adenovirus, hepadnavirus, herpesvirus, poxvirus. The first three are naked and the latter three are enveloped.

2. Naked viruses cause acute infection only. Some enveloped viruses are capable of chronic infection.

3. PEECoRnA: polio, entero, echo, coxsackie, rhino, hepA.

4. VZV and HSV are similar in that they both cause acute vesicular infections with lifelong latency and recurrence. EBV and CMV are similar in that they both cause infectious mononucleosis-type syndromes. CMV and HSV both cause congenital viral infection malformation syndromes.

5. Rhinovirus, RSV, parainfluenza virus, coronavirus, adenovirus. Influenza virus may be included also.

6. Pete Can Float Toward the Coast Backward: picorna, calci, flavi, toga, corona, retro.

7. None. Only enveloped viruses can cause chronic infection.

8. Raspberry Filled Parfaits Are Often Burned: rhabdo, filo, paramyxo, arena, orthomyxo, bunya.

9. Viruses are too small to be seen on light microscopy. On electron microscopy, nearly all naked viruses have an icosahedral-shaped head.

10. Herpesvirus (HSV, VZV, CMV), picornavirus (poliovirus, enteroviruses), flavivirus (encephalitis), togavirus (encephalitis), rhabdovirus (rabies), bunyavirus (encephalitis).


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