VIRUS

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VIRUS
Kuliah I (9 April 2007)

• MIKROBIOLOGI FARMASI I

Dra. Marlina, MS. Apt
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Topik

• 1. Pendahuluan (sejarah, klasifikasi, family,
  stuktur, bentuk, riset/ perkembangan penelitian)
• 2. Influenza (flu burung, avian flu)
• 3. HIV
• 4. Polio, Hepatitis
• 5. Herpes
• 6. Vaksin, antivirus

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Pendahuluan

• Sejarah
• 1883 Adolf Mayer virus pada tembakau
• 1892 Dimitri Ivanowsky menguji hipotesis A.
  Mayer
• 1851-1931 Martinus Beijerinck (Belanda), mulai
  disimpulkan, virus pada tanaman tobacco mosaic
  virus (TMV).
• 1953 Wendell M (USA) mengkristalkan TMV

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• The first virus to be discovered was the tobacco
  mosaic virus (TMV).
• In the 1880s, researchers figured out that
  tobacco plants could catch what appeared to be
  a contagious germ from other, infected tobacco
  plants.
• Finally in the 1930s, TMV was found by
  crystalizing it

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Ciri-ciri virus

• Ukuran sangat kecil (20-300 nm)
• 50x lebih kecil dari bakteri
• Tidak dapat dilihat dengan mikroskop biasa, hanya
  dapat digunakan mikroskop elektron
• Apakah virus makhluk hidup atau bukan?

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Continue..

• Virus hanya mempunyai DNA dan RNA
• Mampu meperbanyak diri, tetapi hanya dalam sel
  hidup (host)
• Dalam Host, dapat bersifat mematikan atau inaktif
• Menggunakan DNA atau RNA nya sendiri untuk
  menginstruksikan sel host membuat salinan2 baru

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• Virus bukan sel
• Virus adalah partikel atau virion yang bentuk
  sangat sederhana dan ukurannya sangat kecil
• Komponen virus sangat simple
• Tidak mampu mensintesis protein dan membentuk ATP
• Jadi, apa sebenarnya virus itu???????

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Struktur dan Bentuk Virus

• Terdiri atas materi genetik (genom) berupa DNA
  atau RNA
• Bentuk DNA atau RNA tergantung pada spesifikasi
  virus
• Bisa tunggal (single stranded) atau ganda (double
  stranded)
• Bentuknya dapat memanjang, melingkar atau lurus

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• Setiap genom diselubungi oleh Kapsid
• Kapsid dan asam nukleat disebut Nukleokapsid
• Kapsid tersusun dari sejumlah besar subunit
  protein yang disebut Kapsomer
• Kapsomer merupakan polipeptida atau kumpulan
  polipeptida
• Setiap kapsomer memiliki molekul protein yang
  berbeda-beda

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Kapsid

• Bentuk kapsid bermacam2
• Batang
• Bulat
• Oval
• Bentuk T
• Contoh TMV, bentuk batang
• Virus polio, bentuk isohedron (mempunyai 20 muka
  segitiga sama sisi dengan 12 sudut dan 30 tepi)

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Macam-macam bentuk virus
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• Bentuk kapsid menentukan bentuk luar virus
• Ada struktur tambahan yang disebut Amplop

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Amplop

• Amplop adalah kapsul pembungkus yang menyelubungi
  kapsid dan tersusun dari bahan lipoprotein yang
  berfungsi membantu virus menginfeksi inangnya
• Contoh virus dengan amplop
• virus flu, virus herpes, virus pada hewan

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Replikasi Virus

• Hanya terjadi dalam host
• Reproduksi virus secara penggandaan (replikasi)
  dari genom
• Gen baru terbentuk dengan menggunakan enzim,
  ribosom, nutrien dari host
• Komponen2 terakumulasi membentuk sejumlah besar
  virion2 yang kemudian meninggalkan inangnya untuk
  menginfeksi inang baru

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Bakteriofage

• Bakteriofage atau fage digunakan sebagai contoh
  mempelajari replikasi virus
• Bakteriofage atau fage adalah virus yang biasa
  ditemukan dan hidup dalam tubuh E. coli
• Virus ini pertama kali ditemukan tahun 1915

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Replikasi virus

• Ada 2 jenis replikasi
• 1. melalui siklus litik
• 2. melalui siklus lisogenik

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Replikasi virus hewan

• Tahap2
• 1. Penetrasi
• 2. Replikasi
• 3. Transkripsi
• 4. Sintesis protein
• 5. Perakitan protein
• 6. Pelepasan virus baru

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Penetrasi

• Virus masuk seperti ditelan oleh inangnya
  (endositosis)
• Beberapa virus memiliki permukaan protein yang
  berhubungan kepada reseptor membran plasma sel
  inang dan merangsang endositosis
• Tipe lain memiliki amplop dan dapat melebur
  dengan membran sel inang
• Dalam sel inang, genom virus dilepas ke dalam
  sitoplasma

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Replikasi

• Genom membentuk tiruan beberapa kali

Transkripsi
Genom virus digunakan sebagai blueprint membentuk
messenger RNA
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Sintesis protein

• Dalam sitoplasma sel inang, mRNA digunakan untuk
  pembentukan protein virus

Perakitan protein
Genom virus dan enzim dikelilingi olwh lapisan
protein
Pelepasan
Setelah terbentuk virus sempurna, virus keluar
dari sel inang melalui embentukan tuna (budding)
pada membran sel inang
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contoh penyakit pada manusia yang disebabkan
oleh virus

• Influenza
• Demam
• Cacar
• Gondong
• Campak
• Campak jerman (Rubella)
• Poliomyelitis

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• Demam kuning (yellow fever)
• Hepatitis (A, B, C, D, E)
• Cacar air (penyebab varicella)
• AIDS (penyebab HIV
• Herpes simplex

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Beberapa penyakit pada hewan yang disebabkan oleh
virus

• Tetelo, penyebab New Castle disease virus
• Penyakit kuku dan mulut pada sapi dan kerbau
• Penyakit kanker pada ayam yang disebabkan oleh
  Rous Carcoma virus
• Rabies, menyerang anjing, kucing, monyet.
  Penyebab virus rabies

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Beberapa penyakit pada tumbuhan yang disebabkan
oleh virus
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Genom virus

• 100s of sequenced viral genomes
• 3 to gt100 genes
• RNA or DNA
• double stranded or single stranded
• linear (RNA and DNA)
• circular (DNA only)
• single stranded (RNA mostly, rare for DNA)
• Encode envelop, capsid proteins, often a
  replicase, often one or more genes to disable
  host
• Utilize host cell machinery for replication
• Important in recombinant DNA technology

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• Viruses, like bacteria, are found everywhere.
• They are, however, much smaller.
• Before the germ theory of disease was
  established, people thought that diseases were
  caused by poisons and, since the Latin term for
  poison is "virus," that is the name adopted.
  Pasteur often referred to bacteria as viruses.
• Then, as research showed that microorganisms were
  the actual cause of infectious diseases, various
  pathogenic microbes were identified and removed
  from the category of poisons (or viruses).
• Since viruses do not propogate well in an
  artificial culture medium, observing them did not
  take place until the "golden age of
  microbiology,"

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• Viruses can grow only inside of cells. They cant
  multiply in the environment and are to some
  extent dead objects there. Theres a running
  debate about whether viruses are alive or dead
  because, when you crystallize them and they
  behave like crystalline proteins, theyre like
  dead chemical objects. (Bacteria, on the other
  hand, are definitely living organisms.) And yet,
  when allowed into a cell, they can hijack the
  total metabolism of the cell (in minutes in a
  bacterium, hours in a mammalian cell) and
  completely reprogram that cell so that the only
  thing it can do effectively anymore is make more
  viruses.
• Because viruses multiply inside cells, they are
  faced with the problem of exiting from the cell.

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• When viruses pass from one organism to another,
  they adapt to that host viruses of humans adapt
  to the specific ways that humans interact.
• Polio is another virus that has been virtually
  eliminated by vaccination and very conscious
  activity on the part of the World Health
  Organization.

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• The smallest viruses are smaller than ribosomes
  in cells, and the largest are so big that theyre
  just barely visible under the highest power of
  magnification possible with a regular light
  microscope.
• A single virus particle is called a virion, and
  is made of nucleic acid (either single or
  double-stranded RNA or DNA depending on what kind
  of virus it is) in a protein shell.
• The viral nucleic acid (RNA or DNA) is one
  molecule (one chromosome), consisting of from
  four to several thousand genes in length.

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• The surrounding protein coat that encloses the
  viral nucleic acid is called a capsid, and its
  shape, its protein structure, is specific to each
  kind (species?) of virus.
• An isolated virion is inert it has no metabolic
  equipment, thus cannot do any chemical reactions
  on its own.
• Virions can be separated into separate nucleic
  acid and protein components

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• Viruses are obligate intracellular parasites
• Viruses are capable of replicating many copies of
  themselves, which then go infect other cells.
  However, each type of virus has a limited range
  of host cells.
• Viruses use a sort of chemical lock and key
  mechanism to join to receptor sites on the
  surface of their host cell, thus the host may be
  only one or or several closely-related species
• Some viruses can insert themselves (their DNA)
  into their hosts genetic material, stay there,
  and replicate along with host DNA when the host
  cells do mitosis.

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• Herpes viruses are especially known for this, and
  it is thought that some forms of cancer may be
  caused in this way.
• Bacterial viruses (viruses that infect bacteria
  yes, such things really do exist!) are known as
  bacteriophages.
• Many plant viruses are passed in the usual way by
  contamination from another infected plant
• Many animal viruses have a slightly different way
  of entering or leaving their host cells

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Klasifikasi Virus

• Viruses can be divided into at least six general
  classes based on the type of nucleic acid they
  contain and on the pathways they use to express
  their genetic information.
• Viruses with ds-DNA The flow of information is
  ds-DNA to mRNA to protein. This classic pathway
  is seen in all higher forms of life.
• Viruses with ss-DNA The flow of information is
  ss-DNA to ds-DNA to mRNA to protein. The ss-DNA
  must first be changed into ds-DNA done by
  cellular enzymes after the viral nucleic acid
  enters the cell. Thereafter, the flow of
  information is the same as in Class 1.
• Viruses with ds-RNA The flow of information is
  ds-RNA to mRNA to protein. This class of viruses
  presents a unique problem because ds-RNA is not
  found in normal cells. Thus, no enzyme is present
  in a cell to direct the transcription of ds-RNA
  molecules. To solve this problem, these viruses
  direct the synthesis of a special enzyme that
  will transcribe mRNA from the ds-RNA molecule.
  This enzyme is packaged inside the viral capsid
  along with the ds-RNA.
• Viruses with ss-RNA of the same polarity as mRNA
  (simply called ss-RNA) The information flow is
  mRNA to protein. The viral nucleic acid acts
  directly as mRNA once inside the cell and
  completely bypasses the regular step of
  transcription

• .

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• Viruses with ss-RNA of the opposite polarity from
  mRNA (simply called ss-RNA-) The information
  flow is ss-RNA- to mRNA to protein. The
  information flow is ss-RNA- to mRNA to protein.
  As in class 3, this is a unique situation in
  which a function not found in a normal cell must
  be carried out -- that is, the transcription of
  mRNA from a ss-RNA molecule. It is, therefore,
  necessary to provide a specific enzyme to
  accomplish this task. These viruses carry this
  special enzyme and also direct its formation as
  part of their replication process.
• Viruses with ss-RNA and a special enzyme called
  Reverse Transcriptase or RNA-dependent-DNA
  polymerase Some viruses in this class are
  associated with the induction of cancer in
  animals, and others cause the immunodeficiency
  syndrome (AIDS). These viruses change the genetic
  information on their ss-RNA molecule into a
  ds-DNA molecule, or in other words, move backward
  from the normal flow of genetic information. The
  information flow is ss-RNA to ss-DNA to ds-DNA to
  mRNA to protein. The enzyme reverse transcriptase
  is needed for the step from ss-RNA to ss-DNA.
  Normal cellular enzymes are able to direct the
  other functions. When the ds-DNA is formed, it
  may insert into the DNA of the host cell. Under
  certain conditions that are not well understood,
  some of the information in this inserted DNA may
  be transcribed and direct changes in the cell
  that may cause cancer. Under other conditions the
  inserted DNA may be transcribed and direct the
  information of new virus particles.

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• One of the biggest questions about viruses is,
  Are they alive? Consider that viruses
• unlike living organisms, can be crystallized,
  then be put back together and be viable (this
  would kill a bacterium),
• like living organisms, have genetic programming,
  can mutate, and can evolve (this is the reason we
  cant make an AIDS vaccine that will always
  work),
• unlike living organisms, cannot reproduce
  independently, but like living organisms, can
  reproduce, and
• eukaryotic virus genes are more similar to
  eukaryotic genes, and prokaryotic virus genes are
  more similar to prokaryotic genes, suggesting
  that viruses may have evolved from fragments of
  cellular nucleic acids that acquired special
  packaging.

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MAIN VIRUSES AFFECTING HUMANS

• Influenza flu (from the influence of the
  stars astrology) There are a number of
  strains and the virus mutates a lot. It infects
  the respiratory system, usually with fever
  (vomiting?). It has a 48-hr incubation after
  exposure.

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• Mumps
• It infects the salivary (parotid) glands in the
  neck, also (especially in post-puberty patients)
  possibly other organs like testes, but usually
  doesnt cause sterility. It is most common in
  children, and spread by saliva.

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• Measles Rubeola (rubeo red)
• This is common measles. Symptoms and signs
  include white spots on mucous membranes in the
  mouth, red spots/rash on the skin, and fever and
  cold symptoms. It is spread by saliva and nasal
  secretions.
• German measles Rubella
• If this infects a pregnant woman (or from
  vaccination of it), it can cross the placenta and
  cause birth defects (first trimester). The
  patient is infective from one week before onset
  of the rash until one week after it fades. The
  symptoms are often milder than regular measles.

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• Herpes viruses (herpes creeping)
• smallpox This makes pus-filled pox. People who
  had the more mild cowpox didnt get this, which
  led to the development of vaccinations
• chickenpox This stays in the persons DNA
  (hiding in certain nerve cells) and can come
  back as shingles, Herpes zoster or Varicella
  zoster. As shingles, this virus is in the CNS,
  follows a nerve, and thus, is painful. Chickenpox
  symptoms include mild headache, fever, and a
  rash consisting of raised pox filled with
  fluid. The lesions are no longer infective when
  crusted over
• cold sores These stay in the persons DNA
  (hiding in mucous membrane around the lip area)
  and can come back during periods of stress.
  Herpes simplex type I is the responsible agent.
• genital herpes This is caused by Herpes simplex
  type II, and is spread by sexual contact.

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• Hepatitis (hepato liver)
• There are a number of different, related diseases
  which go by the name of hepatitis.
• human papiloma virus HPV genital warts
• This is another sexually-transmitted virus.
  Frequently a person develops several of these in
  close proximity. The warts begin as soft,
  moist, reddish swellings on either the external
  genital area or within the urethra (males) or
  vagina (females) and grow rapidly. At least one
  type inserts its DNA into the DNA of the host
  cells, and all are difficult to treat/control.
  Women who get this frequently end up with
  cervical cancer several years later,
  necessitating surgery to remove part or all of
  the uterus.

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• rabies
• May be found in some dogs and bats. It is also
  know as hydrophobia because the animal has
  trouble drinking, and so appears to be afraid of
  water.
• Rabies invades the CNS, leading to paralysis and
  death. The virus is present in the saliva of
  infected mammals, and is often transferred by a
  bite. In US, most cases are from the bites of
  wild animals since dogs are vaccinated.
• Beware of behavior changes in wild animals
  skunks or other nocturnal animals active in
  daytime, or wild animals lacking normal fear of
  humans. Rabies is more likely from carnivores
  rabbits, etc. usually dont have rabies.
• Current treatment involves vaccines around the
  site of the bite and intramuscular.

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• Warts
• These are contagious, and are most frequent in
  older children.
• Their appearance and size are influenced by
  location and degree of irritation (most frequent
  on sites subject to trauma like fingers, elbows,
  knees plantar warts on soles of feet are
  flattened by pressure).
• Warts may persist by autoinoculation. Usually,
  complete regression in several months is common
  with or without treatment, but some may last for
  years.
• Most do not become malignant.

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• AIDS acquired immunodeficient syndrome HIV
  human immunodeficiency virus
• AIDS is transferred in blood and other fluids.
  Tears during sexual contact (especially likely in
  anal sex because the rectum not designed for
  that) are often an entry point, as well as IV
  drug users sharing needles. As mentioned, AIDS
  infects/kills cells of the immune system that
  help fight off other infections. Thus the person
  often dies from secondary infections.
• The AIDS virus contains RNA as its genetic
  material and an enzyme called reverse
  transcriptase.
• AIDS virus can do reverse transcription to go
  from its RNA to DNA, which is inserted into the
  persons cells to control replication of more
  virus.

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Anti-viral drugs

• Many nations, as well as the World Health
  Organization, are working to stockpile anti-viral
  drugs in preparation for a possible pandemic.
  Oseltamivir (trade name Tamiflu) is the most
  commonly sought drug, since it is available in
  pill form. Zanamivir (trade name Relenza) is also
  considered for use, but it must be inhaled. Other
  anti-viral drugs are less likely to be effective
  against pandemic influenza.
• Both Tamiflu and Relenza are in short supply, and
  production capabilities are limited in the medium
  term. Some doctors say that co-administration of
  Tamiflu with probenecid could double supplies.
  14
• There also is the potential of viruses to evolve
  drug resistance. Some H5N1-infected persons
  treated with oseltamivir have developed resistant
  strains of that virus.

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• Peramivir is a pharmaceutical drug used to viral
  infections. Like zanamivir and oseltamivir,
  peramivir is a neuraminidase inhibitor, acting as
  a transition-state analogue inhibitor of
  influenza neuraminidase and thereby preventing
  new viruses from emerging from infected cells.
  Experimental data indicate that peramivir may
  have useful activity against many viruses of
  interest, including H5N1 (avian bird flu)
  ,hepatitis B, polio, measles and smallpox. HHS
  Secretary Mike Leavitt announced on January 4,
  2007 that the Department has awarded a 102.6
  million, four-year contract to BioCryst
  Pharmaceuticals, Inc. for advanced development of
  their influenza antiviral drug, peramivir.

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influenza virus

• There are three genera of influenza virus,
  identified by antigenic differences in their
  nucleoprotein and matrix protein
• Influenzavirus A are the cause of all flu
  pandemics and are known to infect humans, other
  mammals and birds (see also avian influenza),
• Influenzavirus B are known to infect humans and
  seals,
• Influenzavirus C are known to infect humans and
  pigs.

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• Flu spreads around the world in seasonal
  epidemics, killing millions of people in pandemic
  years and hundreds of thousands in non-pandemic
  years.
• Three influenza pandemics occurred in the 20th
  century and killed tens of millions of people,
  with each of these pandemics being caused by the
  appearance of a new strain of the virus in
  humans.
• Often, these new strains result from the spread
  of an existing flu virus to humans from other
  animal species.
• Since it first killed humans in Asia in the
  1990s, a deadly avian strain of H5N1 has posed
  the greatest risk for a new influenza pandemic.
  However, this virus has not mutated to spread
  easily between people.

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• Vaccinations
• Vaccinations against influenza are most commonly
  given to high-risk humans in industrialised
  countries and to farmed poultry.
• The most common human vaccine is the trivalent
  flu vaccine that contains purified and
  inactivated material from three viral strains.
  Typically this vaccine includes material from two
  influenza A virus subtypes and one influenza B
  virus strain.
• A vaccine formulated for one year may be
  ineffective in the following year, since the
  influenza virus changes rapidly over time and
  different strains become dominant. Antiviral
  drugs can be used to treat influenza, with
  neuraminidase inhibitors being particularly
  effective.

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Marine viruses

• Most abundant biological entity anywhere in
  ocean. At surface, 1010 viruses/liter, 5-25X
  bacterial abundance numerous species
• Infect marine eubacteria and archaea
• Evidence suggests widespread lysogeny entry into
  lytic cycle rare but may be triggered by
  pollutants
• Contribute to mortality of marine bacteria,
  10-50 cells killed, has effect on food chain
• Viral decay UV light, hydrolysis
• Transduction?

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Avian flu

• Avian flu (also "bird flu", "avian influenza",
  "bird influenza"), means "flu from viruses
  adapted to birds", but is sometimes mistakenly
  used to refer to both other flu subsets (such as
  H5N1 flu) or the viruses that cause them (such as
  H5N1)
• "Bird flu" is a phrase similar to "Swine flu",
  "Dog flu", "Horse flu", or "Human flu" in that it
  refers to an illness caused by any of many
  different strains of flu viruses such that the
  strain in question has adapted to the host.
  "Avian flu" differs in being named after an
  entire vertebrate class with 8,80010,200
  species. All known avian flu viruses belong to
  the species of virus called Influenza A virus.
  All subtypes (but not all strains of all
  subtypes) of Influenza A virus are adapted to
  birds, which is why for many purposes avian flu
  virus is the Influenza A virus (note that the "A"
  does not stand for "avian").

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• Genetic factors in distinguishing between "human
  flu viruses" and "avian flu viruses" include
• PB2 (RNA polymerase) Amino acid (or residue)
  position 627 in the PB2 protein encoded by the
  PB2 RNA gene. Until H5N1, all known avian
  influenza viruses had a Glu at position 627,
  while all human influenza viruses had a lysine.
• HA (hemagglutinin) Avian influenza HA bind
  alpha 2-3 sialic acid receptors while human
  influenza HA bind alpha 2-6 sialic acid
  receptors. Swine influenza viruses have the
  ability to bind both types of sialic acid
  receptors.

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• H5N1 has evolved into a flu virus strain that
  infects more species than any previously known
  flu virus strain, is deadlier than any previously
  known flu virus strain, and continues to evolve
  becoming both more widespread and more deadly
  causing a leading expert on avian flu to publish
  an article titled "The world is teetering on the
  edge of a pandemic that could kill a large
  fraction of the human population" in American
  Scientist.
• He called for adequate resources to fight what he
  sees as a major world threat to possibly billions
  of lives.
• Since the article was written, the world
  community has spent billions of dollars fighting
  this threat with limited success.
• It is a race between an exceptionally fast
  mutating virus and modern scientific research
  capabilities, with the winner of the race still
  in doubt.