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Teach Cough Hygiene Everywhere/Basic info on viruses

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A virus is a biological agent that reproduces inside the cells of living hosts. When infected by a virus, a host cell is forced to produce many thousands of identical copies of the original virus, at an extraordinary rate. Unlike most living things, viruses do not have cells that divide; new viruses are assembled in the infected host cell. Over 2,000 species of viruses have been discovered.

A virus consists of two or three parts: all viruses have genes made from either DNA or RNA, long molecules that carry the genetic information; all have a protein coat that protects these genes; and some have an envelope of fat that surrounds them when they are not within a cell. Viruses vary in shape from the simple helical and icosahedral to more complex structures. Viruses are about 100 times smaller than bacteria, and it would take 30,000 to 750,000 of them, side by side, to stretch to 1 centimeter (0.39 in).

Viruses spread in many different ways. Plant viruses are often spread from plant to plant by insects and other organisms, known as vectors. Some viruses of animals are spread by blood-sucking insects. Each species of virus relies on a particular method. Whereas viruses such as influenza are spread through the air by people when they cough or sneeze, others such as norovirus, which are transmitted by the faecal-oral route, contaminate hands, food and water. Rotavirus is often spread by direct contact with infected children. HIV is one of several major viruses that are transmitted during sex. The origins of viruses is unclear: some may have evolved from plasmids—pieces of DNA that can move between cells—while others may have evolved from bacteria.

Viral infections often cause disease in humans and animals, however they are usually eliminated by the immune system, conferring lifetime immunity to the host for that virus. Antibiotics have no effect on viruses, but antiviral drugs have been developed to treat life-threatening infections. Vaccines that produce lifelong immunity can prevent some viral infections.

Origins

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Viruses are found wherever there is life and have probably existed since living cells first evolved. The origin of viruses is unclear because they do not form fossils, so molecular techniques have been the most useful means of hypothesising how they arose. However, these techniques rely on the availability of ancient viral DNA or RNA but most of the viruses that have been preserved and stored in laboratories are less than 90 years old.[1][2] Molecular methods have only been successful in tracing the ancestry of viruses that evolved in the 20th century.[3]

There are three main theories of the origins of viruses:[4][5]

  • Regressive theory: Viruses may have once been small cells that parasitised larger cells. Over time, genes not required by their parasitism were lost. The bacteria rickettsia and chlamydia are living cells that, like viruses, can reproduce only inside host cells. They lend credence to this theory, as their dependence on parasitism is likely to have caused the loss of genes that enabled them to survive outside a cell.[6]
  • Cellular origin theory: Some viruses may have evolved from bits of DNA or RNA that "escaped" from the genes of a larger organism. The escaped DNA could have come from plasmids—pieces of DNA that can move between cells—while others may have evolved from bacteria.[7]
  • Coevolution theory: Viruses may have evolved from complex molecules of protein and DNA at the same time as cells first appeared on earth and would have been dependent on cellular life for many millions of years.

Discovery

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Scanning electron micrograph of HIV-1 viruses, coloured green, budding from a lymphocyte

In 1884, the French microbiologist Charles Chamberland invented a filter, (known today as the Chamberland filter or Chamberland-Pasteur filter), that has pores smaller than bacteria. Thus, he could pass a solution containing bacteria through the filter and completely remove them from the solution.[8] Russian biologist Dimitri Ivanovski used this filter to study what is now known to be the tobacco mosaic virus. His experiments showed that the crushed leaf extracts of infected tobacco plants are still infectious after filtration.

At the same time several other scientists proved that, although these agents (later called viruses) were different from bacteria, they could still cause disease, and they were about a hundred times smaller than bacteria. In 1899 The Dutch microbiologist Martinus Beijerinck observed that the agent multiplied only in dividing cells. Having failed to demonstrate its particulate nature he called it a "contagium vivum fluidum" to mean "soluble living germ".[9] In the early 20th century, English bacteriologist Frederick Twort discovered viruses that infect bacteria,[10] and French-Canadian microbiologist Félix d'Herelle described viruses that, when added to bacteria growing on agar, would lead to the formation of whole areas of dead bacteria. Counting these dead areas allowed him to calculate the number of viruses in the suspension.[11]

With the invention of electron microscopy in 1931 by the German engineers Ernst Ruska and Max Knoll came the first images of viruses.[12] In 1935 American biochemist and virologist Wendell Meredith Stanley examined the tobacco mosaic virus and found it to be mostly made from protein.[13] A short time later, this virus was separated into protein and RNA parts.[14] A problem for early scientists was that they did not know how to grow viruses without using live animals. The breakthrough came in 1931, when the American pathologist Ernest William Goodpasture grew influenza and several other viruses in fertilised chickens' eggs.[15] Some viruses could not be grown in chickens' eggs, but this problem was solved in 1949 when John Franklin Enders, Thomas Huckle Weller and Frederick Chapman Robbins grew polio virus in cultures of living animal cells.[16] Over 2,000 species of virus have been discovered.[17]

Structure

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A simplified diagram of the structure of a virus

A virus particle, known as a virion, consists of genes made from DNA or RNA which are surrounded by a protective coat of protein called a capsid.[18] The capsid is made of many smaller, identical protein molecules which are called capsomers. The arrangement of the capsomers can either be icosahedral (20-sided), helical or more complex. There is an inner shell around the DNA or RNA called the nucleocapsid, which is formed by proteins. Some viruses are surrounded by a bubble of lipid (fat) called an envelope.

Size

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Viruses are among the smallest infectious agents, and most of them can only be seen by electron microscopy. Most viruses cannot be seen by light microscopy (in other words, they are sub-microscopic); their sizes range from 20 to 300 Nanometre. They are so small that it would take 30,000 to 750,000 of them, side by side, to stretch to one cm.[18]

Genes

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Genes are made from DNA (deoxyribonucleic acid) and, in many viruses, RNA (ribonucleic acid). The biological information contained in an organism is encoded in its DNA or RNA. Most organisms use DNA, but many viruses have RNA as their genetic material. The DNA or RNA of viruses consists of either a single strand or a double helix.[19]

Viruses reproduce rapidly because they have only a few genes compared to humans who have 20,000–25,000.[20] For example, influenza virus has only eight genes and rotavirus has eleven. These genes encode structural proteins that form the virus particle, or non-structural proteins, that are only found in cells infected by the virus.[21]

All cells, and many viruses, produce proteins that are enzymes called DNA polymerase and RNA polymerase which make new copies of DNA and RNA. A virus's polymerase enzymes are often much more efficient at making DNA and RNA than the host cell's.[22] However, RNA polymerase enzymes often make mistakes, and this is one of the reasons why RNA viruses often mutate to form new strains.[23]

In some species of RNA virus, the genes are not on a continuous molecule of RNA, but are separated. The influenza virus, for example, has eight separate genes made of RNA. When two different strains of influenza virus infect the same cell, these genes can mix and produce new strains of the virus in a process called reassortment.[24]

Protein synthesis

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Diagram of a typical eukaryotic cell, showing subcellular components. Organelles: (1) nucleolus (2) nucleus (3) ribosome (4) vesicle (5) rough endoplasmic reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) smooth ER (9) mitochondria (10) vacuole (11) cytoplasm (12) lysosome (13) centrioles within centrosome (14) virus particle shown to approximate scale

Proteins are essential to life. Cells produce new protein molecules from amino acid building blocks based on information coded in DNA. Each type of protein is a specialist that only performs one function, so if a cell needs to do something new, it must make a new protein. Viruses force the cell to make new proteins that the cell does not need, but are needed for the virus to reproduce. Protein synthesis basically consists of two major steps: transcription and translation.

Transcription is the process where information in DNA, called the genetic code, is used to produce RNA copies called messenger RNA (mRNA). These migrate through the cell and carry the code to ribosomes where it is used to make proteins. This is called translation because the protein's amino acid structure is determined by the mRNA's code.

Some RNA genes of viruses function directly as mRNA without further modification. For this reason, these viruses are called positive-sense RNA viruses.[25] In other RNA viruses, the RNA is a complementary copy of mRNA and these viruses rely on the cell's or their own enzyme to make mRNA. These are called negative-sense RNA viruses. In viruses made from DNA, the method of mRNA production is similar to that of the cell. The species of viruses called retroviruses behave completely differently: they have RNA, but inside the host cell a DNA copy of their RNA is made. This DNA is then incorporated into the host's, and copied into mRNA by the cell's normal pathways.[26]

Life-cycle

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Life-cycle of a typical virus, following infection of a cell by a single virus, hundreds of offspring are released

When a virus infects a cell, the virus forces it to make thousands more viruses. It does this by making the cell copy the virus's DNA or RNA, making viral proteins, which all assemble to form new virus particles.[27]

There are six basic, overlapping stages in the life cycle of viruses in living cells:[28]

  • Attachment is the binding of the virus to specific molecules on the surface of the cell. This specificity restricts the virus to a very limited type of cell. For example, the human immunodeficiency virus (HIV) infects only human T cells, because its surface protein, gp120, can only react with CD4 and other molecules on the T cell's surface. Plant viruses can only attach to plant cells and cannot infect animals. This mechanism has evolved to favour those viruses that only infect cells in which they are capable of reproducing.
  • Penetration follows attachment; viruses penetrate the host cell by endocytosis or by fusion with the cell.
  • Uncoating happens inside the cell when the viral capsid is removed and destroyed by viral enzymes or host enzymes, thereby exposing the viral nucleic acid.
  • Replication of virus particles is the stage where a cell uses viral messenger RNA in its protein synthesis systems to produce viral proteins. The RNA or DNA synthesis abilities of the cell produce the virus's DNA or RNA.
  • Assembly takes place in the cell when the newly created viral proteins and nucleic acid combine to form hundreds of new virus particles.
  • Release occurs when the new viruses escape or are released from the cell. Most viruses achieve this by making the cells burst, a process called lysis. Other viruses such as HIV are released more gently by a process called budding.

Effects on the host cell

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The range of structural and biochemical effects that viruses have on the host cell is extensive.[29] These are called cytopathic effects.[30] Most virus infections eventually result in the death of the host cell. The causes of death include cell lysis (bursting), alterations to the cell's surface membrane and apoptosis (cell "suicide").[31] Often cell death is caused by cessation of its normal activity due to proteins produced by the virus, not all of which are components of the virus particle.[32]

Some viruses cause no apparent changes to the infected cell. Cells in which the virus is latent and inactive show few signs of infection and often function normally.[33] This causes persistent infections and the virus is often dormant for many months or years. This is often the case with herpes viruses.[34][35]

Viruses, such as Epstein-Barr virus often cause cells to proliferate without causing malignancy,[36] but viruses, such as papillomaviruses are an established cause of cancer.[37] When a cell's DNA is damaged by a virus and if the cell cannot repair this often triggers apoptosis. One of the results of apoptosis is destruction of the damaged DNA by the cell itself. Some viruses have mechanisms to limit apoptosis so that the host cell does not die before progeny viruses have been produced. HIV, for example, does this.[31]

Viruses and diseases

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For more examples of diseases caused by viruses see Wikipedia's List of infectious diseases
 
Norovirus. Ten Norovirus particles; this RNA virus causes winter vomiting disease. It is often in the news as a cause of gastro-enteritis on cruise ships and in hospitals.

Human diseases caused by viruses include the cold, the flu, chickenpox and cold sores. Serious diseases such as Ebola, AIDS and influenza are also caused by viruses. Many viruses cause little or no disease and are said to be "benign". The more harmful viruses are described as virulent. Viruses cause different diseases depending on the types of cell that they infect. Some viruses can cause life-long or chronic infections where the viruses continue to reproduce in the body despite the host's defence mechanisms.[38] This is common in hepatitis B virus and hepatitis C virus infections. People chronically infected with a virus are known as carriers. They serve as important reservoirs of the virus. If there is a high proportion of carriers in a given population, a disease is said to be endemic.[39]

There are many ways in which viruses spread from host to host but each species of virus uses only one or two. Many viruses that infect plants are carried by organisms; such organisms are called vectors. Some viruses that infect animals and humans are also spread by vectors, usually blood-sucking insects. However, direct animal-to-animal, person-to-person or animal-to-person transmission is more common. Some virus infections, (norovirus and rotavirus), are spread by contaminated food and water, hands and communal objects and by intimate contact with another infected person,[40] while others are airborne (influenza virus).[41] Viruses such as HIV, hepatitis B and hepatitis C are often transmitted by unprotected sex[42] or contaminated hypodermic needles.[43] It is important to know how each different kind of virus is spread to prevent infections and epidemics.[44]

Diseases of plants

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Peppers infected by mild mottle virus

There are many types of plant virus, but often they only cause a loss of yield, and it is not economically viable to try to control them. Plant viruses are often spread from plant to plant by organisms, known as vectors. These are normally insects, but some fungi, nematode worms and single-celled organisms have been shown to be vectors. When control of plant virus infections is considered economical, (for perennial fruits for example), efforts are concentrated on killing the vectors and removing alternate hosts such as weeds.[45] Plant viruses are harmless to humans and other animals because they can only reproduce in living plant cells.[46]

Bacteriophages

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The structure of a typical bacteriophage

Bacteriophages are viruses that infect bacteria. There are over 5,100 types of bacteriophages. They are important in marine ecology: as the infected bacteria burst, carbon compounds are released back into the environment, which stimulates fresh organic growth. Bacteriophages are useful in scientific research because they are harmless to humans and can be studied easily. These viruses can be a problem in industries that produce food and drugs by fermentation and depend on healthy bacteria. Some bacterial infections are becoming difficult to control with antibiotics, so there is a growing interest in the use of bacteriophages to treat infections in humans.[47]

Host resistance

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Innate immunity of animals

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Animals, including humans, have many natural defences against viruses. Some are non-specific and protect against many viruses regardless of the type. This innate immunity is not improved by repeated exposure to viruses and does not retain a "memory" of the infection. The skin of animals, particularly its surface, which is made from dead cells, prevents many types of viruses from infecting the host. The acidity of the contents of the stomach kills many viruses that have been swallowed. When a virus overcomes these barriers and enters the host, other innate defences prevent the spread of infection in the body. A special hormone called interferon is produced by the body when viruses are present, and this stops the viruses from reproducing by killing the infected cell and its close neighbours. Inside cells, there are enzymes that destroy the RNA of viruses. This is called RNA interference. Some blood cells engulf and destroy other virus infected cells.[48]

Adaptive immunity of animals

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Two rotaviruses: the one on the right is coated with antibodies which stop its attaching to cells and infecting them

Specific immunity to viruses develops over time and white blood cells called lymphocytes play a central role. Lymphocytes retain a "memory" of virus infections and produce many special molecules called antibodies. These antibodies attach to viruses and stop the virus from infecting cells. Antibodies are highly selective and attack only one type of virus. The body makes many different antibodies, especially during the initial infection, however, after the infection subsides, some antibodies remain and continue to be produced, often giving the host life-long immunity to the virus.[49]

Plant resistance

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Plants have elaborate and effective defence mechanisms against viruses. One of the most effective is the presence of so-called resistance (R) genes. Each R gene confers resistance to a particular virus by triggering localised areas of cell death around the infected cell, which can often be seen with the unaided eye as large spots. This stops the infection from spreading.[50] RNA interference is also an effective defence in plants.[51] When they are infected, plants often produce natural disinfectants which kill viruses, such as salicylic acid, nitric oxide and reactive oxygen molecules.[52]

Resistance to bacteriophages

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The major way bacteria defend themselves from bacteriophages is by producing enzymes which destroy foreign DNA. These enzymes, called restriction endonucleases, cut up the viral DNA that bacteriophages inject into bacterial cells.

Prevention and treatment of viral disease in humans and other animals

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Vaccines

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The structure of DNA showing the position of the nucleosides and the phosphorus atoms that form the "backbone" of the molecule

Vaccination is a way of preventing diseases caused by viruses. Vaccines simulate a natural infection and its associated immune response, but do not cause the disease. Their use has resulted in a dramatic decline in illness and death caused by infections such as polio, measles, mumps and rubella.[53] Vaccines are available to prevent over thirteen viral infections of humans[54] and more are used to prevent viral infections of animals.[55] Vaccines may consist of either live or killed viruses.[56] Live vaccines contain weakened forms of the virus, but these vaccines can be dangerous when given to people with weak immunity. In these people, the weakened virus can cause the original disease.[57] Biotechnology and genetic engineering techniques are used to produce "designer" vaccines that only have the capsid proteins of the virus. Hepatitis B vaccine is an example of this type of vaccine.[58] These vaccines are safer because they can never cause the disease.[59]

Antiviral drugs

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Over the past 20 years, the development of antiviral drugs has increased rapidly, mainly driven by the AIDS pandemic. Antiviral drugs are often nucleoside analogues, which are molecules very similar, but not identical to DNA building blocks. When the replication of virus DNA begins, some of these fake building blocks are incorporated. As soon as that happens, replication stops prematurely— the fake building blocks lack the essential features that allow the addition of further building blocks. Thus, DNA production is halted, and the virus can no longer reproduce.[60] Examples of nucleoside analogues are aciclovir for herpes virus infections and lamivudine for HIV and hepatitis B virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral drugs.[61]

 
The guanine analogue aciclovir

Other antiviral drugs target different stages of the viral life cycle. HIV is dependent on an enzyme called the HIV-1 protease for the virus to become infectious. There is a class of drugs called protease inhibitors, which bind to this enzyme and stop it from functioning.[62]

Hepatitis C is caused by an RNA virus. In 80% of people infected, the disease becomes chronic, and they remain infectious for the rest of their lives unless they are treated. There is an effective treatment that uses the nucleoside analogue drug ribavirin combined with interferon.[63] The treatment for chronic carriers of the hepatitis B virus by a similar strategy using lamivudine is being developed.[64] In both diseases, the ribavirin stops the virus from reproducing and the interferon kills any remaining infected cells.

HIV infections are usually treated with a combination of antiviral drugs, each targeting a different stage in the virus's life-cycle. There are drugs that prevent the virus from attaching to cells, others that are nucleoside analogues and some poison the virus's enzymes that it needs to reproduce.[62] The success of these drugs is proof of the importance of knowing how viruses reproduce.

Notes

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  1. ↑ Shors. p. 16
  2. ↑ Topley and Wilson pp. 18–19
  3. ↑ Liu, Y., Nickle, D.C., Shriner, D., Jensen, M.A., Learn, G.H. Jr, Mittler, J.E., Mullins, J.I. (2004) "Molecular clock-like evolution of human immunodeficiency virus type 1".Virology. 10;329(1):101-8, PMID 15476878
  4. ↑ Shors pp. 14–16
  5. ↑ Topley and Wilson pp.11–21
  6. ↑ Topley and Wilson p. 11
  7. ↑ Topley and Wilson pp. 11–12
  8. ↑ Shors pp. 76–77
  9. ↑ Topley and Wilson p. 3
  10. ↑ Shors p. 589
  11. ↑ D'Herelle, F. Res. Microbiol. 2007 Sep;158(7):553–4. Epub 2007 Jul 28. "On an invisible microbe antagonistic toward dysenteric bacilli": brief note by Mr. F. D'Herelle, presented by Mr. Roux. 1917. PMID 17855060
  12. ↑ From Nobel Lectures, Physics 1981-1990, (1993) Editor-in-Charge Tore Frängsmyr, Editor Gösta Ekspång, World Scientific Publishing Co., Singapore
  13. ↑ Stanley, W.M., Loring, H.S., (1936) "The isolation of crystalline tobacco mosaic virus protein from diseased tomato plants" Science, 83, p.85 PMID 17756690
  14. ↑ Stanley, W.M., Lauffer, M.A. (1939) "Disintegration of tobacco mosaic virus in urea solutions" Science 89, pp. 345–347 PMID 17788438
  15. ↑ Goodpasture, E.W., Woodruff, A.M., Buddingh, G.J. (1931) "The cultivation of vaccine and other viruses in the chorioallantoic membrane of chick embryos" Science 74, pp. 371–372 PMID 17810781
  16. ↑ Rosen, F.S.(2004) "Isolation of poliovirus—John Enders and the Nobel Prize" New England Journal of Medicine, 351,pp. 1481–83 PMID 15470207
  17. ↑ Shors p. 78
  18. ↑ a b Topley and Wilson pp. 33–55
  19. ↑ Shors pp. 54–61
  20. ↑ International Human Genome Sequencing Consortium (2004) "Finishing the euchromatic sequence of the human genome" Nature 431, p. 931–945 PMID 15496913
  21. ↑ Shors p. 73
  22. ↑ Shors pp. 32–34
  23. ↑ Shors p. 510
  24. ↑ Shors p. 327
  25. ↑ Topley and Wilson pp. 75–82
  26. ↑ Shors pp. 248–250
  27. ↑ Shors pp. 11–12
  28. ↑ Shors pp. 47–67
  29. ↑ Collier pp. 115–146
  30. ↑ Collier p. 115
  31. ↑ a b Roulston A, Marcellus RC, Branton PE (1999). "Viruses and apoptosis". Annu. Rev. Microbiol. 53: 577–628. doi:10.1146/annurev.micro.53.1.577. PMID 10547702. Retrieved 2008-12-20.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ↑ Alwine JC (2008). "Modulation of host cell stress responses by human cytomegalovirus". Curr. Top. Microbiol. Immunol. 325: 263–79. PMID 18637511. {{cite journal}}: |access-date= requires |url= (help)
  33. ↑ Sinclair J (2008). "Human cytomegalovirus: Latency and reactivation in the myeloid lineage". J. Clin. Virol. 41 (3): 180–5. doi:10.1016/j.jcv.2007.11.014. PMID 18164651. Retrieved 2008-12-20. {{cite journal}}: Unknown parameter |month= ignored (help)
  34. ↑ Jordan MC, Jordan GW, Stevens JG, Miller G (1984). "Latent herpesviruses of humans". Ann. Intern. Med. 100 (6): 866–80. PMID 6326635. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  35. ↑ Sissons JG, Bain M, Wills MR (2002). "Latency and reactivation of human cytomegalovirus". J. Infect. 44 (2): 73–7. doi:10.1053/jinf.2001.0948. PMID 12076064. Retrieved 2008-12-20. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  36. ↑ Barozzi P, Potenza L, Riva G, Vallerini D, Quadrelli C, Bosco R, Forghieri F, Torelli G, Luppi M (2007). "B cells and herpesviruses: a model of lymphoproliferation". Autoimmun Rev. 7 (2): 132–6. doi:10.1016/j.autrev.2007.02.018. PMID 18035323. Retrieved 2008-12-20. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  37. ↑ Subramanya D, Grivas PD (2008). "HPV and cervical cancer: updates on an established relationship". Postgrad Med. 120 (4): 7–13. doi:10.3810/pgm.2008.11.1928. PMID 19020360. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)
  38. ↑ Shors p. 483
  39. ↑ Topley and Wilson p. 766
  40. ↑ Shors p. 118
  41. ↑ Shors p.117
  42. ↑ Shors p. 119
  43. ↑ Shors p.123
  44. ↑ Shors pp. 16–19
  45. ↑ Shors p. 584
  46. ↑ Shors pp. 562–587
  47. ↑ Shors pp. 588–604
  48. ↑ Shors pp. 146–158
  49. ↑ Shors pp.158–168
  50. ↑ Dinesh-Kumar, S.P., Wai-Hong Tham, Baker, B.J., (2000) "Structure—function analysis of the tobacco mosaic virus resistance gene N" PNAS 97, 14789-94 PMID 11121079
  51. ↑ Shors pp. 573–576
  52. ↑ Soosaar, J.L., Burch-Smith, T.M., Dinesh-Kumar, S.P. (2005) "Mechanisms of plant resistance to viruses" Nat. Rev. Microbiol. 3, pp. 789–98 PMID 16132037
  53. ↑ Shors pp. 171–185
  54. ↑ Shors p. 183
  55. ↑ Pastoret, P.P., Schudel, A.A., Lombard, M. (2007) "Conclusions—future trends in veterinary vaccinology". Rev. Off. Int. Epizoot. 26, pp. 489–94, 495–501, 503–9. PMID 17892169
  56. ↑ Shors p. 172
  57. ↑ Thomssen, R. (1975) "Live attenuated versus killed virus vaccines". Monographs in allergy 9, pp. 155–76. PMID 1090805
  58. ↑ Shors p. 174
  59. ↑ Shors p. 180
  60. ↑ Shors p. 427
  61. ↑ Shors p. 426
  62. ↑ a b Shors p. 463
  63. ↑ Witthoft, T., Moller, B., Wiedmann, K.H., Mauss, S., Link, R., Lohmeyer, J., Lafrenz, M., Gelbmann, C.M., Huppe, D., Niederau, C., Alshuth, U. (2007) "Safety, tolerability and efficacy of peginterferon alpha-2a and ribavirin in chronic hepatitis C in clinical practice: The German Open Safety Trial." J Viral Hepat. 14, pp. 788–796. PMID 17927615
  64. ↑ Rudin, D., Shah, S.M., Kiss, A., Wetz, R.V., Sottile, V.M. (2007) "Interferon and lamivudine vs. interferon for hepatitis B e antigen-positive hepatitis B treatment: meta-analysis of randomized controlled trials." Liver Int. 9, pp. 1185–93. PMID 17919229

References

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  • Collier, Leslie; Balows, Albert; Sussman Max (1998) Topley and Wilson's Microbiology and Microbial Infections ninth edition, Volume 1, Virology, volume editors: Mahy, Brian and Collier, Leslie. Arnold. ISBN 0340663162
  • Shors, Teri (2008). Understanding Viruses. Jones and Bartlett Publishers. ISBN 0763729329
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