Bi 1 The Biology and Biophysics of Viruses

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Bi 1The Biology and Biophysics of Viruses

• Lecture 1
• Monday March 30, 2009
• Organization of the Course

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Why Bi 1?

• Biology became part of the Caltech core
  curriculum in the mid-1990s.
• 220 freshman
• 35 Bio majors take Bi 8/9 (two course intro to
  molecular and cellular biology)
• 165 freshman take Bi 1

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Topic for Bi 1 since 2007The Biology and
Biophysics of Viruses

• Goal Introduce biological concepts from a
  quantitative, molecular, chemical and biophysical
  perspective.
• No memorization (open book problem sets,
  exams).
• Focus on a topic critical to human health
  viruses (HIV in particular).
• An opportunity to use what youve learned to
  address a real world problem.
• Important to ask questions (PJB Office hours
  Monday after class or by appointment).

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By the end of the course, students will gain a
basic understanding of many issues affecting
todays world e.g.,

• Evolution
• Recombinant DNA technology, biotechnology
• Stem Cell Research
• Gene therapy
• Viral outbreaks (e.g., bird flu)
• Why biology needs physics, math, chemistry,
  computer science, etc. and why these fields needs
  biology
• Possible careers in fields that use biology

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What we will NOT cover

• Clinical aspects of AIDS and other viral
  diseases, social/political issues surrounding
  HIV/AIDS
• Many interesting fields of biology

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Head TA Damien Soghoian
Office Hours Tuesdays 3pm, 153 Broad
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The Bi 1 homepage

• http//www.its.caltech.edu/bi1
• Includes
• List of TAs, office hours
• A glossary
• Links to relevant websites
• Lecture notes, problem sets
• Course information, announcements, policies

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Moodle

• Weekly homework surveys
• courses.caltech.edu
• To join Bi1 class, youll need the codeword
• see head TA for codeword

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Student/faculty conference Monday April
6http//arc.caltech.edu/sfc2009.php

• 800 - 825 - Opening
• 830 - 925 - Core Curriculum Task Force
• 930 - 1025 - Undergraduate Research
• 1030 - 1155 - Student Experience
• 1200 - 1255 - Lunch
• 100 - 155 - Honor Code
• 200 - 255 - Humanities and Social Sciences
• 315 - 425 - Options
• We will have class as usual on Apr 6, but will
  post a podcast of the lecture on the course
  website so you can attend the SFC.

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Clickers

• We will use clickers (interactive response
  pads) to assess success in conveying key
  concepts.
• We will NOT use clickers to take attendance.
• Your responses are anonymous -- will not affect
  your grade.

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Clicker question

• My major is (or will probably be)
• 1. Chemistry
• 2. Math
• 3. Physics
• 4. Engineering
• 5. Geology
• 6. Computer Science

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Clicker question

• I am glad to be taking Bi 1.
• 1. Agree strongly
• 2. Agree somewhat
• 3. Disagree
• 4. Disagree strongly and am very annoyed to have
  to take this course

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Clicker question

• I have had taken one or more Biology courses in
  high school.
• 1. YES, 2 years in high school including AP
  Biology.
• YES, 1 year in high school.
• NO, but I took Biology in junior high.
• NO.

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Clicker question

• Which is correct?
• 1. RNA --gt DNA --gt Protein
• 2. Protein --gt RNA --gt DNA
• 3. DNA --gt RNA --gt Protein
• 4. DNA lt--gt RNA --gt Protein

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Clicker question

• HIV and other viruses are susceptible to
  antibiotics.
• 1. True
• 2. False

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Plagues and pestilence

• History shaped by epidemics
• Bubonic plague in 14th century killed 1/3 of
  Asian and 1/2 of European population (20 million
  deaths).
• 16th century Conquistadors conquered America with
  measles and small pox.
• 1700s European navigators introduce syphilis,
  tuberculosis and whooping cough to South Pacific
  Islands. Population of Hawaii reduced by almost
  90 by 1860.
• Flu epidemic in 1918-19 killed 20-40 million
  (more than died in WWI).

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Ignorance/blame about disease is nothing new

• Christians blamed Jews for bubonic plague
  outbreaks in 14th century.
• 15-16th centuries Italians called syphilis The
  French Disease. French called it The Italian
  Disease.
• 1930s Cholera in New York was blamed on the
  Irish.
• Early 20th century Polio in US said to be
  caused by Italian immigrants.

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CDC definition of AIDS

• A Acquired a virus received from someone else
• I Immune an individuals natural protection
  against disease-causing microorganisms
• D Deficiency a deterioration of the immune
  system
• S Syndrome a group of signs and symptoms that
  together define AIDS as a human disease

(Centers for Disease Control and Prevention
Atlanta, GA)
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What is AIDS?

• HIV infection is not AIDS (is HIV disease)
• AIDS is umbrella term for 26 known diseases and
  symptoms
• AIDS diagnosis if meet three conditions
• Have one or more of known diseases/symptoms
• CD4 T cell count lt200/µL
• What is CD4? What are T cells?
• Test positive for HIV What do HIV tests detect?

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HIVs (there are many) are related to Simian
Immunodeficiency Viruses (SIV)
SIVsm

• Three groups of HIV-1 M Main O Outlier N
  New
• Group M HIV-1 is responsible for 99 of AIDS
  cases worldwide. M is divided into 10 clades.
• HIV-2 (related to SIVsm) less prevalent than
  HIV-1.
• We will concentrate on Group M HIV-1.
• HIV-1 is related to SIVcpz. SIV is relatively
  benign, whereas HIV is lethal.

HIV-2
O
SIVcpz
M
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HIV-1, HIV-2, and SIVsIn natureHIV-1 and
HIV-2 infect humans.HIV-1-related CPZ viruses
infect chimps.SIVs infect African monkeys. In
laboratoriesHIV-1 infects chimpanzees, but does
not cause disease. HIV-1 does not infect old
world monkeys.Asian macaques infected by some
SIV and HIV-2 strains develop AIDS-like disease.
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World-wide prevalence of HIV (July 2008)
People living with HIV/AIDS 33 million
http//en.wikipedia.org/wiki/ImageHIV_Epidem.png
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Early history of HIV/AIDS

• 1884-1924 -- (New) estimate for when SIVcpz
  crossed into humans
• 1959 -- Earliest known AIDS case a Bantu man in
  the Republic of Congo
• 1981 -- first AIDS cases reported among
  homosexual males in US
• 1982 -- AIDS in hemophiliacs, transfusion
  patients, IV drug users
• 1983 -- AIDS in US heterosexuals majority of
  AIDS in Central Africa affects heterosexuals
• 1983 -- Virus causing AIDS isolated by groups
  led by Luc Montagnier (France) and Robert Gallo
  (US) (SARS virus isolated in 2 weeks in 2003 by
  international consortium of 13 labs)
• 1985 -- Blood test to detect HIV
• 1987 -- AZT licensed for use in AIDS patients
• 1996 -- anti-HIV drugs (HAART) reduce AIDS
  death rates

Highly Active Anti-Retroviral Therapy
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10 leading causes of death in US in adults 25-44
years old
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Impact of AIDS on life expectancy in five African
countries, 19702010
70
65
60
Botswana
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South Africa
Life expectancy at birth (years)
50
45
Swaziland
40
35
Zambia
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Zimbabwe
25
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19701975
19801985
19901995
20002005
19751980
19851990
19952000
20052010
Source United Nations Population Division
(2004). World Population Prospects The 2004
Revision, database.
4.1
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What is a virus?

• Viruses are small (compared with bacteria)
  infectious replicating objects that can cause
  disease in plants, animals, humans. 5x108
  rhinoviruses (common cold) will fit on the head
  of a pin.
• Viruses are parasites -- they live inside cells
  of their host animal or plant and reproduce by
  forcing their host to make new viruses.
• Newly-made viruses leave host cell and infect
  similar cells.
• All viruses have a protein coat that encloses
  genetic material (DNA or RNA). Some also have a
  membrane (envelope) around the protein coat.
• Viruses use host cell machinery to make their
  components (proteins, carbohydrates, membranes),
  so they are harder to target with drugs than such
  as bacteria or fungi (self-sufficient pathogens).

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The genetic material in a virus can be DNA or RNA
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Why dont antibiotics work against viruses?

• Antibiotics interfere with metabolic processes in
  bacteria. Metabolic processes in bacteria
  (prokaryotes) and in us (eukaryotes) are
  different.
• Example penicillin interferes with the
  production of bacterial cell walls. Eukaryotic
  cells dont have cell walls (neither do
  viruses).
• Viruses use host cell machinery to undergo
  metabolic processes -- hard to specifically
  target a viral metabolic process.

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DNA viruses follow the Central Dogma DNA --gt
RNA --gt Protein
transcription translation
Most RNA viruses also follow part of the Central
Dogma RNA --gt Protein
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HIV is a RetrovirusRetroviruses do NOT follow
the Central Dogma

• Retroviruses a subset of RNA viruses that
  reverse usual flow of genetic information within
  host cell
• Reverse transcription of viral RNA into viral
  DNA
• RNA --gt DNA --gt RNA --gt Protein
• Three subfamilies of retroviruses
• Oncoviruses (cause cancer)
• Feline leukemia virus, Rous Sarcoma Virus, Mouse
  Mammary Tumor Virus
• Lentiviruses (slow viruses)
• HIV-1 HIV-2, Feline Immunodeficiency Virus
  (cats), Visna virus (sheep), caprine
  arthritis-encephalitis virus (goats), SIV
  (nonhuman primates)
• Spumavirus (not associated with human disease)

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(For exogenous retrovirus start here)
Maturation
Binding Membrane Fusion
Overview of Retroviral Life Cycle
Uncoating Reverse Transcription
Budding
Expression Membrane Targeting
Nuclear transport Integration
(For endogenous retrovirus start here)
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Some believe that HIV does not cause AIDS

• 1987 to present Peter Duesberg (UC Berkeley)
  believes there is no single causative agent of
  AIDS, but disease is a collection of
  non-infectious deficiencies associated with drug
  use, malnutrition, parasitic infections, other
  specific risks. (www.duesberg.com)
• 2000-2002 South African President Thabo Mbeki
  made statements that HIV does not cause AIDS, and
  that AIDS does not exist (gt5 million people in
  South Africa are HIV-positive).

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HIV causes AIDS

• http//www.meds.com/hiv/hivindex3.html
• See also Durban declaration (signed by gt5000
  HIV/AIDS scientists and physicians, released in
  July 2000) for evidence that HIV causes AIDS
• http//www.thebody.com/atn/346/declaration.html
  A few compelling facts
• Data from matched groups of homosexual males and
  hemophiliacs shows that only those infected with
  HIV develop AIDS.
• Only HIV-positive mothers transmit HIV to
  fetuses and only HIV-positive newborns develop
  AIDS. HIV-negative newborns from HIV-positive
  mothers do not develop AIDS.
• Laboratory and health-care workers with no known
  risk factors have developed AIDS after exposure
  to HIV.

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Kochs postulates have been satisfied

• Causative agent must be found in all cases of the
  disease.
• It must be isolated from the host and grown in
  pure culture.
• It must reproduce the original disease when
  introduced into a susceptible host.
• It must be found in the experimental host so
  infected.

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http//www.its.caltech.edu/bi1/syllabus_2009.html

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• You will need to fill out an add card if
• you register late
• want to change sections
• want to switch to P/F grading
• must be done before Drop Day (5/20/09)
• Either Damien or I can sign this.

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Why study HIV?

• The Human Immunodeficiency Virus (HIV)
  epidemic has spawned a scientific effort
  unprecedented in the history of infectious
  disease research. This effort has merged aspects
  of clinical research, basic molecular biology,
  immunology, cell biology, epidemiology, and
  mathematical modeling in ways that have not been
  seen before. The ever unfolding discoveries of
  novel aspects of HIV-host interaction have been
  accompanied by (and often have resulted from)
  novel interactions among researchers in the
  disparate disciplines.
• Coffin, J.M. 1999. Molecular Biology of HIV. In
  The Evolution of HIV, ed. K.A. Crandall.
  Baltimore Johns Hopkins University Press.

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Extra slides
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New AIDS cases and deaths due to AIDS have been
reduced in the US
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Figure 9-12
Number of HIV cases worldwide at end of 2002
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Consider Africa.
Worldwide, HIV has spread to 70 million people,
killed 30 million and is estimated to infect 40
million more in the next decade.

• Sub-Saharan Africa has 67 of worlds HIV/AIDS
  cases but only 10-11 of worlds population --
  home to 87 of 2.3 million children living with
  HIV/AIDS.
• South Africa has highest number of people living
  with HIV/AIDS in the world (5.5 million in May
  2006) and almost one in five South African adults
  are HIV positive.
• National HIV prevalence rate in Swaziland is
  33, the highest in the world.

Fact Sheet The Global HIV/AIDS epidemic (May
2006) Kaiser Family Foundation
www.kff.org/hivaids
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Figure 9-22
Opportunistic infections and malignancies in AIDS
patients
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Symptoms of AIDS(each symptom can be caused by
another disease cant rely on symptoms to
diagnose AIDS)

• Rapid weight loss
• Dry cough
• Recurring fevers, night sweats
• Unexplained fatigue
• Swollen lymph glands
• Diarrhea that lasts more than a month
• White spots on tongue, in mouth, or throat
  (thrush)
• Pneumonia
• Red, brown, pink or purplish blotches on skin or
  inside mouth, nose, or eyelids (Kaposi Sarcoma)
• Memory loss, depression, other neurological
  disorders

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Killing viruses

• Can inactivate viruses using physical and
  chemical agents
• Heat (e.g., boiling water) alters structures of
  proteins and nucleic acids
• UV radiation crosslinks thymines in nucleic acids
  (more in problem set 1)
• Formaldehyde combines with free amino groups on
  nucleic acids
• Metals and phenol react with proteins in the
  viral capsid
• Chlorine combines chemically with viral nucleic
  acid
• Detergents denature viral proteins
• Antiviral drugs (rare because they can interfere
  with essential chemical reactions in the host)