Bi 1
“The Biology and Biophysics of Viruses”
Lecture 1
Monday March 28, 2011
Organization of the Course
Topic for Bi 1 since 2007:
“The 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 you’ve learned to address a real
world problem.
• Important to ask questions (PJB Office hours Wednesday
after class or by appointment).
By the end of the course, students will gain a basic
understanding of many issues affecting today’s world; e.g.,
• Evolution
• Recombinant DNA technology, biotechnology
• Stem Cell Research
• Gene therapy
• Viral outbreaks (e.g., swine flu)
• Why biology needs physics, math, chemistry, computer science,
engineering, etc. and why these fields needs biology
• Possible careers in fields that use biology
What we will NOT cover
• Clinical aspects of AIDS and other viral
diseases, social/political issues surrounding
HIV/AIDS
• Many interesting fields of biology
Head TA: Linda Song
Office Hours: Tuesdays 2:30 pm; 153 Broad
The Bi 1 homepage:
http://www.its.caltech.edu/~bi1
Includes:
List of TAs, office hours
A glossary
Links to relevant websites
Lecture notes, lecture recordings, problem sets
Course information, announcements, policies
Moodle
• Weekly homework surveys
courses.caltech.edu
• To join Bi1 class, you’ll need the codeword:
jenner
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.
Clicker question:
My
1.
2.
3.
4.
5.
6.
major is (or will probably be)
Chemistry
Math
Physics
Engineering
Geology
Computer Science
Clicker question:
I have had taken one or more Biology courses in
high school.
1.
YES, ≥2 years in high school including AP
Biology.
2. YES, 1 year in high school.
3. NO, but I took Biology in junior high.
4. NO.
Clicker question:
Which is correct?
1.
2.
3.
4.
RNA --> DNA --> Protein
Protein --> RNA --> DNA
DNA --> RNA --> Protein
DNA <--> RNA --> Protein
Clicker question:
HIV and other viruses are susceptible to
antibiotics.
1.
True
2. False
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).
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.
CDC* definition of AIDS
A = Acquired = a virus received from someone else
I = Immune = an individual’s 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)
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 <200/µL
What is CD4? What are T cells?
– Test positive for HIV
What do HIV tests detect?
HIVs (there are many) are related to
Simian Immunodeficiency Viruses (SIV)
SIVsm
HIV-2
O
SIVcpz
M
• 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-1, HIV-2, and SIVs
In nature:
HIV-1 and HIV-2 infect humans.
HIV-1-related CPZ viruses infect chimps.
SIVs infect African monkeys.
In laboratories:
HIV-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.
World-wide prevalence of HIV (July 2008)
People living with HIV/AIDS: ~33 million
http://en.wikipedia.org/wiki/Image:HIV_Epidem.png
Millions
Estimated number of adult and child deaths
due to AIDS globally, 1990–2007
3.0
2.5
2.0
1.5
1.0
0.5
0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Year
This bar indicates the range around the estimate
Figure 5.3
2008 Report on
the
global AIDS
epidemic
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
10 leading causes of death in US in adults 25-44 years old
Impact of AIDS on life expectancy in five African countries, 1970–
2010
70
65
60
Botswana
55
Life
expectancy
at birth
(years)
50
45
South Africa
Swaziland
40
35
30
25
Zambia
Zimbabwe
20
1970–1975
1980–1985
1990–1995
2000–2005
1975–1980
1985–1990
1995–2000
2005–2010
Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database.
4.1
HIV Prevalence by Age
Pregnant women, Durban, South Africa
Percent testing positive
75
50
25
0
0 8 16 24 32 40 48 52
Age
Fundiswe Chonco, Mopo Leshwedi, Thumbi Ndung’u et al, unpublished
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 (selfsufficient pathogens).
The genetic material in a virus can be DNA or RNA
Why don’t 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 don’t have
cell walls (neither do viruses).
• Viruses use host cell machinery to undergo
metabolic processes -- hard to specifically target
a viral metabolic process.
DNA viruses follow the
“Central Dogma”
DNA --> RNA --> Protein
transcription
translation
Most RNA viruses also
follow part of the
Central Dogma
RNA --> Protein
HIV is a Retrovirus
Retroviruses 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 --> DNA --> RNA --> 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)
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 (>5 million people in South Africa are HIVpositive).
HIV causes AIDS
http://www.meds.com/hiv/hivindex3.html
See also Durban declaration (signed by >5000 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 HIVpositive newborns develop AIDS. HIV-negative newborns from HIVpositive mothers do not develop AIDS.
• Laboratory and health-care workers with no known risk factors
have developed AIDS after exposure to HIV.
Koch’s postulates have been satisfied
1. Causative agent must be found in all cases of the
disease.
2. It must be isolated from the host and grown in pure
culture.
3. It must reproduce the original disease when
introduced into a susceptible host.
4. It must be found in the experimental host so
infected.
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 (5/18/11)
Either Linda or I can sign this.
Extra slides
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.
New AIDS cases and deaths due to AIDS have been reduced
in the US
Number of HIV cases worldwide at end of 2002
Figure 9-12
Worldwide, HIV has spread to 70 million people,
killed 30 million and is estimated to infect 40 million
more in the next decade.
Consider Africa….
• Sub-Saharan Africa has ~67% of world’s HIV/AIDS cases but
only 10-11% of world’s 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
Opportunistic infections and malignancies in AIDS patients
Figure 9-22
Symptoms of AIDS
(each symptom can be caused by another disease; can’t 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
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)