Bi 1“The Biology and Biophysics of

Viruses”

Lecture 1Monday 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 glossaryLinks to relevant websitesLecture notes, lecture recordings, problem setsCourse 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.

My major is (or will probably be) 1. Chemistry2. Math3. Physics4. Engineering 5. Geology6. 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. RNA --> DNA --> Protein2. Protein --> RNA --> DNA3. DNA --> RNA --> Protein4. DNA <--> RNA --> Protein

Clicker question:

HIV and other viruses are susceptible to antibiotics.

1. True

2. False

Clicker question:

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.

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

CDC* definition of AIDS

* (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 HIVWhat do HIV tests detect?

• Three groups of HIV-1M = MainO = OutlierN = 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.

O

HIV-2

SIVsm

M

SIVcpz

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

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)

http://en.wikipedia.org/wiki/Image:HIV_Epidem.png

People living with HIV/AIDS: ~33 million

Figure

2008 Report on the global AIDS epidemic

Estimated number of adult and child deaths due to AIDS globally, 1990–2007

Year

Mill

ions

0

1.5

2.0

2.5

3.0

1990 19911992 1993 1994 19951996 19971998 19992000 2001 200220032004 2005 2006 2007

0.5

1.0

This bar indicates the range around the estimate

5.3

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, Impact of AIDS on life expectancy in five African countries, 1970–20101970–2010

Life expectancy at birth (years)

Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database.

Botswana

South Africa

Swaziland

Zambia

Zimbabwe

1970–1975 1975–1980

1980–19851985–1990

1990–19951995–2000

2000–20052005–2010

70

65

60

55

50

45

40

35

30

25

20

4.1

HIV Prevalence by AgePregnant women, Durban, South Africa

Fundiswe Chonco, Mopo Leshwedi, Thumbi Ndung’u et al, unpublished

0 8 16 24 32 40 48 52

0

25

50

75

Age

Per

cent

test

ing

posi

tive

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).

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 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 --> 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 HIV-positive).

HIV causes AIDShttp://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 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.

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

Figure 9-12

Number of HIV cases worldwide at end of 2002

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

Worldwide, HIV has spread to 70 million people, killed 30 million and is estimated to infect 40 million more in the next decade.

Figure 9-22

Opportunistic infections and malignancies in AIDS patients

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)