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Animal Viruses

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Last revised: Tuesday, April 18, 2000
Ch. 18 in Prescott et al, Microbiology, 4th Ed.
Note: These notes are provided as a guide to topics the instructor hopes to cover during lecture. Actual coverage will always differ somewhat from what is printed here. These notes are not a substitute for the actual lecture!
Copyright 2000. Thomas M. Terry

Animal Viruses

Types of infection

Viruses in animal cells show a variety of infection patterns:

Example: Poliovirus (+RNA)

  1. See text section 8.15
  2. + RNA virus, 7500 bases long (code for 2500 AAs max)
  3. pico-RNA virus, very small
  4. See Web information on picornaviruses
  5. simple icosahedral shell
  6. RNA makes single polyprotein, then cleaved to ca. 20 smaller proteins: include 4 virion proteins, RNA polymerase (replicase), protease
  7. replication is cytoplasmic
  8. Replicase makes "-" strand from "+" template, uses these to make more "+" strands
  9. RNA gets covalently linked to VPg protein (22 AA)
  10. Host RNA & protein synth. inhibited by destruction of cap-binding protein requd. for translation.
  11. Medical: epidemic in late 1940's, early 1950's. 1.5 cases/100 people. Salk vaccine licensed 1951, immediate impact. By early 60's disease gone.
  12. Virus was waterborne disease, transmitted by drinking or swimming. Can be eliminated by proper chlorine treatment.

Example: Influenza (- RNA)

  1. see text pp. 28-7289
  2. member or orthomyxoviruses (myxo = interact with mucus in respiratory tract)
  3. most lethal pathogen of 20th century. Epidemic of 1918-19 killed 20 million people!
  4. Transmitted by person-to-person contact, mainly by droplets from coughing and sneezing.
  5. Virus attacks mucous membranes of upper respiratory tract, sometimes lungs.
  6. Symptoms: 3-7 days fever, chills, fatigue, headache, muscular aches. Most serious problems due to bacteria that invade while defences are weak. Death may occur in infants, elderly.
  7. enveloped virus, not icosahedral. Virion contains 8 pieces of ss "-" RNA, each codes for separate protein.
  8. View influenza virus electron micrographs
  9. Virus membrane has several protein: Hemagluttinin, Neuraminidase.
  10. Virion also carries RNA-dependendent RNA polymerase and RNA endonuclease
  11. Entry: by endocytosis. Then RNA replicates in nucleus. New "+" RNA migrates to cytoplasm, is translated. from 8 RNAs get 10 proteins (2 proteins are cleaved).
  12. Exit by budding out. Viruses shed for long time.
  13. Antigenic shift occurs every few years. Thought to result from mixing of different virus strains in same cell, recombination of surface protein genes to give new arrangements.
  14. Vaccines not good for more than a few years because of new strains. Usually only recommend for those at most risk
  15. Aspirin not good for flu; possible link with Reye's syndrome in children especially.

Example: Herpes viruses (ds DNA)

  1. large group of ds DNA viruses. See text section 8.19
  2. Diseases include: cold sores, venereal herpes, chickenpox, shingles, infectious mononucleosis, and cancer
  3. Able to become latent for long time; e.g. in peripheral neurons.
  4. Virion contains DNA (150 kbp), icosahedral shell, and envelope. Enough DNA to code for about 70 proteins.
  5. View EM of herpesvirus
  6. View model of herpesvirus virion
  7. View movies of stages of Herpes Virus (requires Flash 3 plug-in)
  8. Infection: attach to cell receptors, fuse virus membrane with cell membrane, release inner particle, travel to nucleus. Then, uncoat virus DNA. DNA synthesis occurs in nucleus. Proteins synthesized in cytoplasm, travel back to nucleus for assembly.
  9. Virions bud through inner membrane of nucleus to outside of cell.

Example: HIV (Retrovirus)

  1. See Section 8.21.
  2. HIV virus as example: Virion contains 2 identical "+" RNAs, also enzyme reverse transcriptase
  3. View 3-D diagram of HIV virion
  4. RNA is about 9 kb in length, could code for 3000 AA, about 10 proteins.
  5. RNA could serve as mRNA but doesn't. Instead, travels to nucleus. One of two RNA's is copied by reverse transcriptase into ss DNA, then into ds DNA (again by reverse transcriptase, which now acts as DNA replicase)
  6. View animations showing HIV virus uncoating and replication (from Doc Kaiser's Microbiology Home Page Copyright 1999 Gary E. Kaiser)
    1. Animation showing adsorption of HIV.
    2. Animation showing penetration of HIV.
    3. Animation showing the action of reverse transcriptase.
    4. Animation showing provirus formation.
    5. Animation showing replication of HIV.
    6. Animation showing maturation and release of HIV.
    7. Animation summarizing the life cycle of HIV.
  7. Primer for DNA synthesis is special tRNA brought by virion from last host.
  8. DNA integrates into host chromosome
  9. Virus DNA then transcribed & translated into viral proteins. RNA is packaged at cell membrane into new viruses by budding from cell
  10. View TEM of HIV particles budding out of host cell
  11. Medical: some retroviruses cause cancer; e.g. Rous sarcoma virus

Human Immunodefiency Virus (HIV) and AIDS

  1. AIDS first recognized in 1981. Over 300,000 cases reported in U.S., over 8 million in Africa, over 33.6 million infected world-wide as of 1999 (WHO statistics)

    People newly infected with HIV in 1999
    Total
    Adults
    Women
    Children <15 years
    5.6 million
    5 million
    2.3 million
    570 000
    Number of people living with HIV/AIDS
    Total
    Adults
    Women
    Children <15 years
    33.6 million
    32.4 million
    14.8 million
    1.2 million
    AIDS deaths in 1999
    Total
    Adults
    Women
    Children <15 years
    2.6 million
    2.1 million
    1.1 million
    470 000
    Total number of AIDS deaths since the
    beginning of the epidemic
    Total
    Adults
    Women
    Children <15 years
    16.3 million
    12.7 million
    6.2 million
    3.6 million

  2. Transmission: sexual activity, especially with multiple sex partners. Also contaminated blood, needles, hospitals. Not just a disease of homosexuals! In Africa (most # cases) about equal # of male and female victims.
  3. AIDS lowers immune system's ability to respond to other infections, allows opportunistic pathogens to invade body. Most common infection is pneumonia (lung infection) caused by Pneumocystis (2/3 of all AIDS patients get this at some point).
  4. Host cell for the virus is CD4 (T-helper) cell, needed to activate antibody production. In normal human, CD4 cells account for 70% of total T cells -- in AIDS, number decreases, may reach 0% of T cell pool.
  5. Progress of HIV infection only recently understood. Formerly thought that virus became latent. Now discover that virus is anythig but latent: during infected period (which can last 10 years), body is destroying ~ billion virions/day, and virus is killing about 100 million CD4 T cells a day. HIV virus continues replicating, and body rapidly replenishes lost T cells. Only when lymph nodes wear out does virus gain the upper hand. See handout in class titled "Huge HIV turnover helps explain drug resistance, pathogenicity".
  6. Prognosis: with carefully selected treatments, better than before. Virtually every infected person dies sooner of later, usually within 10 years of infection. No cure known, no vaccine yet available. Virus mutates rapidly, many strain variations. Vaccines being tried, results mixed but preliminary.
  7. Drugs: some types of drugs offer limited success.
    1. AZT (azidothymidine) is analog of thymidine, but is blocked at 3'-position, so no further chain growth possible. These target viral reverse transcriptase enzyme. Should reduce DNA synthesis in treated cells. But eventually, viral mutants resistant to drug arise. Also, long term use of drug can cause toxic side effects.
    2. protease inhibitors. Like many viruses, HIV needs to cleave large protein product into smaller products, using viral protease protein. By inhibiting this enzyme, should block necessary stage in viral replication cycle. Still under development, but resistant viral mutants to these type of drugs have already been found. Still, drug offers promise. See handout article for more details. Safe sex! Caution with sharps. Extra caution in clinical settings!

Viroids and Prions

Creutzfeldt-Jakob disease
  • occurs worldwide and usually becomes evident as dementia.
  • Very rare; afflicts one person in a million. 10 to 15 percent of cases are inherited.
  • Typically begins in 60's with a loss of memory.
  • Over several weeks the mental deterioration progresses to dementia, abnormalities of vision or coordination, rigidity, and involuntary.
  • Death usually occurs within six months, and at necropsy the brain shows a "spongy" texture
  • View section of brain tissue from Creutzfeldt-Jakob autopsy
Mad Cow Disease
  • Cows becomen uncoordinated and unusually apprehensive.
  • Disease traced to use of sheep tissue as food supplement for cows over long period of time in United Kingdom. Practice was begun in late 1970s.
  • Small number of younger humans (mostly in 20s) came down with Creutzfeldt-Jakob disease in mid-1980s in Britain. Never before seen in humans younger than 50s. Suspected cause was eating beef from cattle fed with sheep products.
  • British government banned animal-derived feed supplements in 1988
  • For further reading, visit What the heck is Mad Cow Disease, by Jack Brown, U. of Kansas

Animal defenses against viral infection

Unlike bacteria, animal cells do not make restriction (and modification) enzymes. More complex defenses are used.
Fever: fever is a non-specific response to infection, and can inhibit or significantly slow growth of many infectious agents, including some bacteria and some viruses (see text p. 810).

Interferons:
IF's are low molecular weight proteins, produced by cells in very tiny amounts in response to certain stimuli (e.g. double-stranded RNA). Very species specific; mouse IF won't work in humans. IF genes in cell are usually inhibited, but activated after viral infection, cause cell to produce IF. IF then acts on other cells by binding to specific membrane receptors, triggering activation of genes that help make cell more virus-resistant. Two specific inhibitors:

(1) Oliogo(A) synthetase: after stimulation by ds RNA, leads to activation of endoRNase activity, which can cleave viral RNA
(2) Inactive protein kinase: after stimulation by ds RNA, leads to activation of inihibitor of elongation factor 2 (eF-2) needed for protein synthesis; blocks translation of viral proteins.

Specific Immunity. (Details to be discussed when immune system is discussed). Normally requires 1-2 weeks after initial exposure before significant response appears.
(1) Antibodies produced against viruses can clump virus particles, lead to phagocytic uptake and destruction.
(2) T-cells can identify virus-infected cells by presence of new viral antigens, and T-killer cells can destroy these cells, prevent infection from spreading.

Antiviral chemotherapy. In general, antiviral agents much more difficult to find, much more limited in scope, than antibacterial agents. Why? Bacteria have unique targets not found in animal cell: peptidoglycan, 70S ribosomes. By contrast, animal virus infects human cell, any treatment which harms virus probably harms host as well.

A few successful antiviral drugs. Ex 1: amantadine treats influenza A infections (if given early in infection); blocks penetration and uncoating of virions. Ex 2: acyclovir, prevents herpes infections; after phosphorylation, resembles dGTP and blocks activity of DNA polymerase.

But, drug-resistant virus strains can develop.


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