Because human survival depends on disease resistance, it is natural to have an anthropocentric perspective on evolutionary changes in gene frequencies and neglect that pathogens also evolve . With modern techniques of immunology, biochemistry, and molecular biology, epidemiologists can monitor both the distribution of disease resistance genes and the evolution of virulence genes in infectious organisms. The picture is ominous. Most pathogenic bacteria have become resistant to one or more antibiotics and some appear to be resistant to all major antibiotics. Plasmids, containing multiple resistance genes, move from one bacterial species to another in a natural form of lateral gene transfer that creates transgenic pathogens. We promote this process by including antibiotics in animal feed. If bacteria evolution seems fast compared to human evolution, viral evolution is even faster.
Among human pathogens, influenza virus is remarkable. Its proteins evolve about one million times faster than typical human proteins , a rate that makes the influenza virus a model for evolutionary studies . The spherical virus is surrounded by a lipid bilayer in which two types of viral-encoded proteins, hemagglutinin (H) and neuraminidase (N), project as is shown in the figure at the left. Within the virus are eight separate RNA molecules, each of which encodes an mRNA for a different protein. Checkout the influenza sequence data base.
Influenza viruses evolve in two ways. Antigenic drift is the accumulation of acceptable amino acid replacements primarily in the H and N surface antigens that is driven in part by immune surveillance . These proteins play an important role in the infection and pathogenicity of various influenza strains that have killed millions of people during periodic pandemics. Antigenic shift occurs when two different strains coinfect a cell and the resulting progeny virus contains a random combination of genes from each strain . The sudden antigenic shift to a new strain usually occurs by recombination between a human and an avian or mammalian influenza virus .
Because the three-dimensional structures of the H and N antigens have been determined, it is possible to assess the role of human antibodies in viral protein evolution. By determining the nucleotide sequences of genes obtained from influenza A viruses isolated and preserved over the past fifty years, the molecular evolution of influenza virus has been reconstructed in some detail). This virus evolves so rapidly that a fifty-year-old influenza virus is analogous to a 50-million-year-old fossil!
Assignment: Discuss all of the questions below in your groups. As a group, construct a Concept Map on the "Evolution of Viruses" that incorporates the issues and concepts highlighted by the questions below. This is the one of two assignments this semester for which a group grade will be given. The assignment is due Monday, October 28, 2002 at the beginning of class. Remember that a neat, well organized map will be more effective at communicating your understanding.
1. Familiarize yourself with the structure and epidemiology of influenza virus and its surface proteins. How does the evolutionary response of the pathogen play into the approach to treatment ? Is there any point in trying to produce an influenza vaccine useful for more than a couple of years?
2. The survival strategy of the human influenza virus is to evolve rapidly , but in order to do so it must have a very high mutation rate. If the virus replicates within human cells, how can it have a vastly different mutation rate than the human genomic DNA?
3. Several authors have claimed that the rate of evolution of human influenza virus H antigen is due simply to the high mutation rate and not to natural selection . Their basic argument is that the rate of evolution of the first and second codon positions was not very different from the third. Why would that imply little, if any, selection?
4. Fitch and coworkers and others attribute a majority of the nucleotide substitutions in the hemagglutinin gene to positive selection due to the immune system and provide tests to support their hypothesis over the neutrality hypothesis described above . From the point of view of hypothesis testing, do these tests disprove the neutral evolution hypothesis in this case? Can one predict the evolutionary changes that might occur in future influenza outbreaks?
5. HIV evolves at a rate similar to influenza virus. Rather than move from host to host, HIV evolves within a single host over a decade, producing several lineages and eventually swamping the host immune system before AIDS develops. Infection of new hosts occurs sporadically. Compendia of articles on AIDS can be found in refs. 30 and 31. Compared to the phylogeny of influenza virus isolates based on nucleotide sequence analysis, what would a phylogeny of contemporary HIV isolates look like? What implications does the natural history and evolution of HIV have for therapy (32)? When and where did the AIDS epidemic start.
Among human pathogens, influenza virus is remarkable. Its proteins evolve about one million times faster than typical human proteins , a rate that makes the influenza virus a model for evolutionary studies . The spherical virus is surrounded by a lipid bilayer in which two types of viral-encoded proteins, hemagglutinin (H) and neuraminidase (N), project as is shown in the figure at the left. Within the virus are eight separate RNA molecules, each of which encodes an mRNA for a different protein. Checkout the influenza sequence data base.
Influenza viruses evolve in two ways. Antigenic drift is the accumulation of acceptable amino acid replacements primarily in the H and N surface antigens that is driven in part by immune surveillance . These proteins play an important role in the infection and pathogenicity of various influenza strains that have killed millions of people during periodic pandemics. Antigenic shift occurs when two different strains coinfect a cell and the resulting progeny virus contains a random combination of genes from each strain . The sudden antigenic shift to a new strain usually occurs by recombination between a human and an avian or mammalian influenza virus .
Because the three-dimensional structures of the H and N antigens have been determined, it is possible to assess the role of human antibodies in viral protein evolution. By determining the nucleotide sequences of genes obtained from influenza A viruses isolated and preserved over the past fifty years, the molecular evolution of influenza virus has been reconstructed in some detail). This virus evolves so rapidly that a fifty-year-old influenza virus is analogous to a 50-million-year-old fossil!
Assignment: Discuss all of the questions below in your groups. As a group, construct a Concept Map on the "Evolution of Viruses" that incorporates the issues and concepts highlighted by the questions below. This is the one of two assignments this semester for which a group grade will be given. The assignment is due Monday, October 28, 2002 at the beginning of class. Remember that a neat, well organized map will be more effective at communicating your understanding.
1. Familiarize yourself with the structure and epidemiology of influenza virus and its surface proteins. How does the evolutionary response of the pathogen play into the approach to treatment ? Is there any point in trying to produce an influenza vaccine useful for more than a couple of years?
2. The survival strategy of the human influenza virus is to evolve rapidly , but in order to do so it must have a very high mutation rate. If the virus replicates within human cells, how can it have a vastly different mutation rate than the human genomic DNA?
3. Several authors have claimed that the rate of evolution of human influenza virus H antigen is due simply to the high mutation rate and not to natural selection . Their basic argument is that the rate of evolution of the first and second codon positions was not very different from the third. Why would that imply little, if any, selection?
4. Fitch and coworkers and others attribute a majority of the nucleotide substitutions in the hemagglutinin gene to positive selection due to the immune system and provide tests to support their hypothesis over the neutrality hypothesis described above . From the point of view of hypothesis testing, do these tests disprove the neutral evolution hypothesis in this case? Can one predict the evolutionary changes that might occur in future influenza outbreaks?
5. HIV evolves at a rate similar to influenza virus. Rather than move from host to host, HIV evolves within a single host over a decade, producing several lineages and eventually swamping the host immune system before AIDS develops. Infection of new hosts occurs sporadically. Compendia of articles on AIDS can be found in refs. 30 and 31. Compared to the phylogeny of influenza virus isolates based on nucleotide sequence analysis, what would a phylogeny of contemporary HIV isolates look like? What implications does the natural history and evolution of HIV have for therapy (32)? When and where did the AIDS epidemic start.
Instances of Avian Influenza Infections in Humans
Confirmed instances of avian influenza viruses infecting humans since 1997 include:
H5N1, Hong Kong, Special Administrative Region, 1997: Highly pathogenic avian influenza A (H5N1) infections occurred in both poultry and humans. This was the first time an avian influenza A virus transmission directly from birds to humans had been found. During this outbreak, 18 people were hospitalized and six of them died. To control the outbreak, authorities killed about 1.5 million chickens to remove the source of the virus. Scientists determined that the virus spread primarily from birds to humans, though rare person-to-person infection was noted.
H9N2, China and Hong Kong, Special Administrative Region, 1999: Low pathogenic avian influenza A (H9N2) virus infection was confirmed in two children and resulted in uncomplicated influenza-like illness. Both patients recovered, and no additional cases were confirmed. The source is unknown, but the evidence suggested that poultry was the source of infection and the main mode of transmission was from bird to human. However, the possibility of person-to-person transmission could not be ruled out. Several additional human H9N2 infections were reported from China in 1998-99.
H7N2, Virginia, 2002: Following an outbreak of H7N2 among poultry in the Shenandoah Valley poultry production area, one person was found to have serologic evidence of infection with H7N2.
H5N1, China and Hong Kong, Special Administrative Region, 2003: Two cases of highly pathogenic avian influenza A (H5N1) infection occurred among members of a Hong Kong family that had traveled to China. One person recovered, the other died. How or where these two family members were infected was not determined. Another family member died of a respiratory illness in China, but no testing was done.
H7N7, Netherlands, 2003: The Netherlands reported outbreaks of influenza A (H7N7) in poultry on several farms. Later, infections were reported among pigs and humans. In total, 89 people were confirmed to have H7N7 influenza virus infection associated with this poultry outbreak. These cases occurred mostly among poultry workers. H7N7-associated illness included 78 cases of conjunctivitis (eye infections) only; 5 cases of conjunctivitis and influenza-like illnesses with cough, fever, and muscle aches; 2 cases of influenza-like illness only; and 4 cases that were classified as “other.” There was one death among the 89 total cases. It occurred in a veterinarian who visited one of the affected farms and developed acute respiratory distress syndrome and complications related to H7N7 infection. The majority of these cases occurred as a result of direct contact with infected poultry; however, Dutch authorities reported three possible instances of transmission from poultry workers to family members. Since then, no other instances of H7N7 infection among humans have been reported.
H9N2, Hong Kong, Special Administrative Region, 2003: Low pathogenic avian influenza A (H9N2) infection was confirmed in a child in Hong Kong. The child was hospitalized and recovered.
H7N2, New York, 2003: In November 2003, a patient with serious underlying medical conditions was admitted to a hospital in New York with respiratory symptoms. One of the initial laboratory tests identified an influenza A virus that was thought to be H1N1. The patient recovered and went home after a few weeks. Subsequent confirmatory tests conducted in March 2004 showed that the patient had been infected with avian influenza A (H7N2) virus.
H7N3 in Canada, 2004: In February 2004, human infections of highly pathogenic avian influenza A (H7N3) among poultry workers were associated with an H7N3 outbreak among poultry. The H7N3-associated, mild illnesses consisted of eye infections.
H5N1, Thailand and Vietnam, 2004, and other outbreaks in Asia during 2004 and 2005: In January 2004, outbreaks of highly pathogenic influenza A (H5N1) in Asia were first reported by the World Health Organization. Visit the Avian Influenza section of the World Health Organization Web site for more information and updates.
Symptoms of Avian Influenza in Humans
The reported symptoms of avian influenza in humans have ranged from typical influenza-like symptoms (e.g., fever, cough, sore throat, and muscle aches) to eye infections (conjunctivitis), pneumonia, acute respiratory distress, viral pneumonia, and other severe and life-threatening complications.
Antiviral Agents for Influenza
Four different influenza antiviral drugs (amantadine, rimantadine, oseltamivir, and zanamivir) are approved by the U.S. Food and Drug Administration (FDA) for the treatment of influenza; three are approved for prophylaxis. All four have activity against influenza A viruses. However, sometimes influenza strains can become resistant to these drugs, and therefore the drugs may not always be effective. For example, analyses of some of the 2004 H5N1 viruses isolated from poultry and humans in Asia have shown that the viruses are resistant to two of the medications (amantadine and rimantadine). Monitoring of avian influenza A viruses for resistance to influenza antiviral medications is ongoing.
Cases of Influenza A (H5N1) IN ASIA
Since mid-December 2003, eight Asian countries (Cambodia, China, Indonesia, Japan, Laos, South Korea, Thailand, and Vietnam) have reported an epizootic of highly pathogenic avian influenza in poultry and various other birds caused by influenza A (H5N1). As of February 9, 2004, a total of 23 laboratory-confirmed human cases of influenza A (H5N1) had been reported in Thailand and Vietnam. In 18 (78%) of these cases, the patients died. Clinical experience with avian H5N1 disease in humans is limited (1). The human H5N1 viruses identified in Asia in 2004 are antigenically and genetically distinguishable from the 1997 and February 2003 viruses. To aid surveillance and clinical activities, this report provides a preliminary clinical description of the initial five confirmed cases in Thailand.
Of the five laboratory-confirmed cases in Thailand, four were in male children aged 6--7 years, and one was in a female aged 58 years; all patients were previously healthy (Table). Four patients reported deaths in poultry owned by the patient's family, and two patients reported touching an infected chicken. One patient had infected chickens in his neighborhood and was reported to have played near a chicken cage. None of the confirmed cases occurred among persons involved in the mass culling of chickens.
Patients reported to hospitals 2--6 days after onset of fever and cough (Table). Other early symptoms included sore throat (four), rhinorrhea (two), and myalgia (two). Shortness of breath was reported in all patients 1--5 days after symptom onset. On admission, clinically apparent pneumonia with chest radiograph changes was observed in all patients, with patchy infiltrates in four and interstitial infiltrates in one. Diarrhea and vomiting were not reported. Peripheral leukocytes were normal or decreased, and four patients had lymphopenia (<1,000/µl).>
Of the five laboratory-confirmed cases in Thailand, four were in male children aged 6--7 years, and one was in a female aged 58 years; all patients were previously healthy (Table). Four patients reported deaths in poultry owned by the patient's family, and two patients reported touching an infected chicken. One patient had infected chickens in his neighborhood and was reported to have played near a chicken cage. None of the confirmed cases occurred among persons involved in the mass culling of chickens.
Patients reported to hospitals 2--6 days after onset of fever and cough (Table). Other early symptoms included sore throat (four), rhinorrhea (two), and myalgia (two). Shortness of breath was reported in all patients 1--5 days after symptom onset. On admission, clinically apparent pneumonia with chest radiograph changes was observed in all patients, with patchy infiltrates in four and interstitial infiltrates in one. Diarrhea and vomiting were not reported. Peripheral leukocytes were normal or decreased, and four patients had lymphopenia (<1,000/µl).>