Viruses

Definition

A virus is an infectious agent, often highly host-specific, consisting of genetic material surrounded by a protein coat.

Description

Viruses infect virtually every life form, including humans, animals, plants, fungi , and bacteria . So small that they cannot be seen by a light microscope , viruses range in size from about 30 nanometers (about 0.000001 in) to about 450 nanometers (about 0.000014 in) and are between 100 to 20 times smaller than bacteria. As of the seventh report of the International Committee on Taxonomy of Viruses (ICTV), published in September 2000, known viruses have been assigned to 1550 species in 53 different families. Hundreds of other viruses remain unclassified due to lack of information.

All standard viruses share a general structure of genetic material, or viral genome, and a protein coat, called a capsid. The viral genome is made of either deoxyribose nucleic acid (DNA), the genetic material found in plants and animals, or ribonucleic acid (RNA), a compound plant and animal cells use in protein synthesis. The protein capsid is made of repeating, often-identical subunits known as capsomeres. Viruses are not strictly free-living, as they cannot reproduce on their own. Instead, they use host cell machinery to make both the viral genome and capsids of the newly formed viruses, or virions.

The broad category of viruses also includes unusual infective agents that are missing one or more components of standard viruses. These unconventional viruses include viroids, which exist as circular RNA molecules that are not packaged, and prions, infective particles that contain protein and little or no nucleic acids.

Some viral infections can cause damage to the host cell, resulting in disease to the organism. Other viral infections appear to make the host cells divide uncontrollably, causing the development of cancer . However, many viral infections are asymptomatic and do not result in disease. There are no cures for viral infections, due in part to the difficulty of developing drugs that adversely affect only the virus and not the host. Accordingly, preventative measures such as vaccines play an important role in the treatment of viral diseases.

Function

The primary function of a virus is to infect host cells and create more viruses. The virus does this by taking over the host cell's protein and genetic material-making processes, forcing it to produce the new viruses. Exactly how viruses function in this manner is best understood by examining general viral structure, classification, and reproductive strategies.

Structure and classification

There are three basic structures for standard viral capsids: icosahedral, helical, and complex. Icosahedral capsids are 20-sided, made of triangular capsomere subunits. The points of the triangular subunits join at 12 vertices about the shape. Although exact structure varies from virus type to virus type, a common arrangement is five or six neighboring triangular subunits at each vertex. Some viruses show more than one capsomere arrangement within the capsid. An example of a virus having an icosahedral structure is adenovirus, the virus that can cause acute respiratory disease or viral pneumonia in humans.

The helical viruses have protein subunits that curve about a central axis running the length of the virus. The fanlike arrangement of protein forms a three-dimensional ribbon-shaped structure that covers the viral genome. Some of these capsid structures are stiff and rodlike, while other helical viruses are more flexible. The influenza virus is an example of a virus with a helical capsid structure.

The third type of virus capsid structure is called complex. Although the structure is regular from virus to virus of the same type, the symmetry is not patterned enough to be fully understood. For example, poxvirus, the virus that causes smallpox in humans, has a complex capsid structure of over 100 proteins . Virologists are still trying to determine the exact arrangement of these proteins.

The combination of the capsid and the viral genome is known as a nucleocapsid. Some nucleocapsids are infective in this form and are known as naked viruses. Others require a surrounding lipid membrane derived from the host cell to be infective. The membrane envelope can encompass one or more nucleocapsids and usually contains on its surface at least one viral protein in addition to the host cell components. Viruses of this type are called enveloped or coated viruses.

Viruses are classified according to structural characteristics such as whether the virus genome is made of DNA or RNA. Both of these nucleic acids can form ladder-like structures where each side of the ladder is known as a strand. Viruses are differentiated by whether the DNA or RNA is single or doubled-stranded. The type of capsid structure and whether the virus is naked or enveloped are also considered. A few viral classifications take into account differences in replication strategy.

Replication

The generalized replication cycle for standard viruses begins with the absorption of the virus by the host cell. Absorption involves an interaction between the viral particle and the potential host cell. This is often mediated by a viral protein that is recognized by a binding protein located on the surface of the host cell. Whether the host cell recognizes the viral protein often determines whether a particular cell can or cannot function as a host for a particular virus. For example, the hemagglutin protein of the influenza virus, a viral protein found within the lipid envelope of this coated virus, interacts with a receptor found on the surface of the epithelial cells that line the human respiratory tract.

The next step in the virus replication cycle is penetration and, if necessary, the uncoating of the virus in the host cell. With some coated viruses, the envelope membrane fuses directly with the host membrane, allowing movement of nucleocapsid into the cell's cytoplasm. Other coated viruses are brought into the cell using endosomes, small vesicles of cellular membrane that bud inwardly and are used to move materials into the cell. Due to the lower pH environment of the endosome, the virus coat can fuse with the endosomal membrane to gain access to the cell cytoplasm. Naked viruses are sometimes small enough to move without help through the host cellular membrane, while others use the endosome system.

Once inside the cell, the virus takes over the host cell's protein and nucleic acid production, directing it to produce viral proteins and genomes. For many viruses having a DNA genome, the viral nucleic acid is inserted or integrated directly into the host cell's own DNA, that make up the cell's chromosomes. RNA viruses tend to keep the genome independent from the host cell's genetic material. In either case, the host cell is fooled into using the viral genetic material as the instructions for the production of new infectious virions. In order to ensure that new virions will be formed, viruses often have mechanisms that speed up the protein formation of the host cell. Sometimes the mechanism will be specific for increased production of viral proteins, while others speed up all protein formation.

A special method of producing new virions is employed by retroviruses, such as the human immunodeficiency virus (HIV). These viruses carry their genomes as RNA, but upon entry into the host cell a viral enzyme known as reverse transcriptase converts the viral RNA into DNA, and that molecule is integrated into the host genome. The enzyme is called reverse transcriptase because generally genetic information moves from DNA to RNA copies rather than this reverse process. The integrated DNA is known as a provirus and will be replicated when the host cell divides, to be inherited by the two resulting daughter cells.

After production of the viral proteins and genomes by the host cellular machinery, the capsid is assembled around the genetic material and, for some viruses, a maturation step occurs that is necessary for infectivity. Finally, the new virions are released from the cell. Some coated viruses leave the cell by budding and do not cause the death of the host cell. The budding process is how the virus acquires its lipid membrane envelope. Other viruses lyse, or break down, the host cell membrane. Lysis kills the host cell.

Because of the ability of viruses to carry genetic material into and out of a cell during the reproduction cycle, viruses can function as vectors in genetic engineering . This is done by inserting foreign genetic material into viral genomes and allowing the material to be integrated and expressed in bacteria and animal cells. Viral vectors are often the basis for gene therapies that in their simplest form attempt to cure genetic defects by providing non-mutated copies of a damaged gene to an organism.

Role in human health

Viruses that infect humans cause damage to the infected cells, resulting in outward symptoms seen as human disease. Human viruses gain entry into the body using various routes. Some viruses are transmitted through skin-to-skin contact, such as herpes simplex 1, the virus that causes cold sores. Others are transmitted through exposure to infected blood , the mode of transmission of the hepatitis B virus. Some of the most easily caught viruses, such as varcella-zoster, the virus that causes chicken pox, are transmitted through water droplets suspended in the air. The virus is transmitted when the droplets are breathed in and come in contact with the respiratory tract of the new host.

Gastrointestinal viruses are transmitted through exposure to waste products containing virus particles that has contaminated water or food, and entry into the host's digestive tract through the mouth. Rotavirus, a cause of a diarrheal illness common in children, is transmitted in this manner. Sexually transmitted viruses move from host to host through sexual contact and enter the body by the genitourinary route. HIV and human papilloma virus (HPV) are examples of viruses that are sexually transmitted.

After gaining entry into the host, the response at a cellular level to the viral infection varies with the type of virus and the virulence of the strain. Thus, the response can vary from no apparent change, to detectable changes in the cell, known as cytopathic effects (CPE), to loss of growth control or malignancy. Virulence refers to the ability of a virus to cause disease in a host. Some viruses are highly virulent, causing disease with almost every infection. Measles, rabies, and influenza are virulent viruses. Other less virulent viruses, such as Epstein-Barr virus, which causes mononucleosis, only rarely results in disease symptoms.

Viral infections follow patterns that are specific to the virus. Some infections are localized, that is, restricted to a particular cell type or organ, while others are disseminated throughout the body. Disseminated infections are often propagated through the nervous system or the bloodstream. Infections can be acute, where the patient's immune system self-limits the disease and recovers, or chronic, where the infection continues for a long period of time.

Some viruses have the ability to cause an initial disease state upon infection and then establish a latent or dormant infective state. For example, herpes viruses cause blisters on the skin as a result of their lytic replication, but then establish a latent infection in nerve cells. Upon a stimulus such as exposure to the sun or stress the virus switches back to a lytic cycle, again producing blisters at the site of infection. In this way, the infection can persist for months or even years.

Several viruses, such as human papilloma viruses and Epstein-Barr virus, have been strongly associated with human cancers. The exact role of viruses in malignancy is not yet understood, as environmental and host genetic factors also seem to contribute to the development of tumors. However, it is highly probable that viruses are key triggers for a number of human cancers.

Another effect of viruses on human health is infection by zoonotic viruses, that is, viruses that can be transmitted from an animal host of another species to humans. Some of these viruses are transmitted through a blood-sucking insect intermediary, such as a mosquito, while others are transmitted directly from the infected animal to humans. Many of these viruses raise important public health concerns. An example of a mosquito-transmitted virus is flavivirus that causes West Nile encephalitis in humans. A strain of hantavirus was discovered in 1993 that infects rodents and transmits directly to humans, causing a respiratory illness.

Although most infect plants and animals, a few unconventional viruses cause human disease. The only know human viroid is the delta virus (hepatitis D) that requires co-infection with hepatitis B to be infective. The combined infection of hepatitis B and D causes more severe symptoms than B alone. An example of a human prion-mediated disease is Cruetzfeldt-Jakob disease (CJD), which causes neurological symptoms and is fatal. Of significant concern is a possible variant of CJD reported in Great Britain that affects younger individuals. Although cause and effect has not been conclusively shown, there is suspicion that this disease results from eating beef contaminated with the prion that causes bovine spongiform encephalopathy, or mad cow disease.

Immunological response

When challenged by a viral infection, the human body responds with both anti-bodies and cell-mediated responses to counteract the virus. Antibodies, produced by B lymphocytes, are specific for surface proteins of the virus. When acting as a target for antibodies, such viral proteins are known as antigens. The binding of the antibodies to the viruses can inactive them or target them as foreign for destruction by other components of the immune system. Antibodies can also bind to viral proteins seen in the membrane of infected cells, directing their elimination by the immune system. Antibodies mediate the immunity to reinfection by the same virus. Unfortunately, many viruses have high rates of mutation that alter the surface antigens, rendering the host again susceptible to infection. This process is the reason that one cold does not make a person immune to all rhinoviruses, a virus with at least 95 different serotypes (a characteristic of a virus based on the antibodies that are produced against the surface antigens upon infection).

Non-specific cell-mediated responses are also important to the body's fight against viruses. The production of interferons and cytokines, in particular, is known to help control viral infections. However, the side effects of these molecules, including fever , malaise, fatigue and muscle pains, significantly contribute to the physical symptoms of viral infections.

Diagnosis

In general there are three methods of diagnosing viral disease in humans. Some viruses can be identified clinically, as the infection causes unmistakable outward signs. The blistery pox of the varicella-zoster or chicken pox virus is a good example of a clinically diagnosed viral disease. Viral diseases can also be diagnosed epidemiologically, through known exposure to certain viruses or virus-harboring hosts. However, many virus infections cannot be diagnosed definitively without diagnostic testing.

Diagnostic testing can involve direct detection, using electron microscopy, light microscopy of CPE seen in host cells, detection of viral antigen in patient samples, or detection of the viral genome using the polymerase chain reaction (PCR) test. Effective tests for some viral infections involve indirect detection, generally using cell culture systems to grow the virus in vitro (outside the organism). A final method of diagnosing viral illnesses is serological testing that involves the detection of antibodies against the virus antigen in samples taken at presentation and during convalescence. A serious drawback to traditional serological testing is the amount of time needed to obtain the results. New techniques are being developed, however, that may speed serological tests and make them more useful.

Treatment

Most viral diseases have no cure, so treatment involves easing symptoms and allowing the body's immune system to eliminate the virus. Viruses are not affected by antibiotics , which target bacteria. However, a handful of anti-viral drugs have been developed and many more are in the developmental and drug trial stage. In general, the development of anti-viral drugs has been hampered by the parasitic relationship between viruses and their hosts. It has been difficult to find pharmacological means to kill the virus without harming the host. The speed of viral infection has also been a problem, as viral numbers are so high by the time the infection has symptoms, the drugs have little effect.

Amantadine and rimantiadine are two drugs that have been used successfully against influenza A. These drugs appear to inhibit the absorption of the influenza virus into the epithelial cells of the respiratory tract and, accordingly, are administered prior to infection as a prophylaxis.

Herpes simplex and varicella-zoster infections can be treated with acyclovir, valacyclovir, and famciclovir. Cytomegalovirus infection can be treated with ganciclovir, foscarnet, and cidofovir. All of these drugs are converted into a chemical that interferes with the production of the viral genome. As a viral enzyme produces the genome for these viruses, the chemical does not interfere with the production of genetic material for the host cell.

A number of drugs that inhibit reverse transcriptase have been developed for treatment of HIV. The best known of these is Zidovudine (AZT). The other major target for antiviral HIV drugs is the viral protease, an enzyme that cleaves both viral structural proteins and enzymes apart after formation by the host cell. Because the virus is noninfective if these cleavages do not occur, drugs inhibiting the protease action are effective antivirals. As advances in this field happen quickly, the International AIDS Society/USA Panel provides periodic recommendations as to what drugs given in what combinations have proven to be most effective inn the treatment of AIDS.

Finally, genetically engineered interferon has been used with some success against hepatitis B and C and human papillovirus. However, the severe side effects of this protein, in particular nausea and vomiting, have hampered its usefulness.

KEY TERMS

Capsid —The protein structure of a virus.

Capsomere —The protein subunits of the capsid.

Endosome —A membrane-mediated means of transporting materials from outside to inside the cell.

Genome —The genetic material encoding the genes of an organism.

Nucleocapsid —The combination of the capsid and viral genome.

Prion —An unconventional virus that is made almost entirely of protein.

Reverse transcriptase —A retroviral enzyme that produces DNA copies of genetic information encoded by RNA.

Virion —A single infectious virus particle.

Viroid —An unconventional virus that is made of uncoated RNA.

Zoonotic —A type of virus that primarily infects an insect or animal, but can be transmitted to humans.

Prevention

The most effective method of treatment of viral diseases is prevention of the infection. Vaccines, where the immune system is exposed to non-infective viral antigens to allow the development of protective antibodies, have proven effective in controlling many viral illnesses. Vaccines are made of inactivated (killed) virus, attenuated (weakened) virus, or isolated viral proteins, that are known as subunit vaccines. Vaccines are available for the viruses that cause measles, mumps, rubella, poliomyelitis, rabies, hepatitis A and B, influenza, varicella-zoster (chicken pox) and yellow fever. Many other vaccines are in the developmental or clinical trial stages.

The greatest drawback to vaccines is the inability of the protection to counter the same virus that has altered its antigens through mutation. Thus, viruses that undergo rapid mutation are difficult to control using vaccination . One solution used for influenza is to create a new vaccine every season against the viruses that are predicted to be responsible for upcoming flu outbreaks. Although this is an imperfect system, influenza vaccination is instrumental in shortening epidemics and protecting the populations most at risk for complications, including the chronically ill, the elderly, and health care workers (primarily to prevent transmitting infection to those as risk).

A second preventative measure is the avoidance of infection by blocking transmission at the point of viral entry. This is done through the isolation of infected patients and avoiding contact with infected biological material such as lesions, blood, and airborne particles through the use of gloves, masks, and other barriers. Health care providers must practice careful hygiene of patients, including immediate removal of vomit or diarrhea , and thorough hand washing. These measures are taken equally to avoid patient-to-provider and providerto-patient transmission of viruses. For zoonotic viruses, transmission can be reduced through pesticide control of the insect or animal reservoir of the disease.

Common diseases and disorders

Several hundred different viruses infect humans. The viruses that occur chiefly in humans can be categorized as respiratory, enteric, exanthematous, hepatitis, or persistent. The most common respiratory viruses include the rhinoviruses (the common cold ) and the influenza viruses. Common enteric viruses include polioviruses (now rare because of vaccination), coxsachie viruses (herpangina), and epidemic gastroenteritis viruses such as rotaviruses. Rubeola (measles) and rubella (German measles) are two common exanthematous viruses.

Hepatitis viruses type A through E are known, with type A most often responsible for epidemics of the disease. Many of the persistent viruses are quite widespread and include cytomegalovirus (usually asymptomatic), Epstein-Barr virus (mononucleosis), Herpes simplex virus (cold sores and genital herpes ), human herpes virus type 6 (roseola), human papilloma virus (warts), and varicella-zoster virus (chicken pox and shingles).

Zoonotic viruses, that chiefly infect insects or animals, with humans as minor or accidental host, are generally rarer. The diseases caused by these viruses are limited to areas that can support the insect or animal host as well as humans. Rabies is the most widespread of these diseases. Flaviviruses (yellow and dengue fever), bunyaviruses (California encephalitis and Hantavirus pulmonary syndrome), and filoviruses such as ebola (hemorrhagic fever) are other examples of zoonoitic viruses that cause human disease.

Human disease caused by nonconventional viruses is very rare. The most common is CJD, a prion-mediated disease that occurs in one in a million individuals. Hepatitis D is the only known human viroid, and it requires co-infection with hepatitis B. Other diseases caused by nonconventional viruses are kuru and Gerstmann-Sträussler-Scheinker syndrome (GSS), both caused by prions.

Resources

BOOKS

Brooks, George F. et al. "General Properties of Viruses" and "Pathogenesis & Control of Viral Disease." In Medical Microbiology. Appleton & Lange, 1998.

Collier, Leslie and John Oxford. Human Virology. New York: Oxford University Press, 2000.

PERIODICALS

Carpenter, Charles et al. "Antiretroviral Therapy in Adults" JAMA 283 (January 2000): 381–90.

Mahoney, M.C. "Adult immunization—influenza vaccine" American Family Physician 69 (May 2000): 2901–2902.

"Provider-to-Patient Transmission" American Journal of Nursing 99 (May 1999): 17.

OTHER

"Virology." On-line Textbook of Microbiology and Immunology. University of South Carolina School of Medicine, Department of Microbiology. <http://www.med.sc.edu:85/book/welcome.htm> (March 15, 2001).

Michelle L. Johnson, M.S.