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Bi 1“The Biology and Biophysics of Viruses” : 

1 Bi 1“The Biology and Biophysics of Viruses” Lecture 1 Monday March 26, 2007 Organization of the Course

Why Bi 1? : 

2 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

Most recent Bi 1 topic: “Drugs and the Brain” (Professor Henry Lester)New topic for Bi 1 this year:“The Biology and Biophysics of Viruses” : 

3 Most recent Bi 1 topic: “Drugs and the Brain” (Professor Henry Lester)New topic for Bi 1 this year:“The Biology and Biophysics of Viruses” Goal: Introduce biological concepts from a quantitative, molecular, chemical and biophysical perspective. Focus on a topic critical to human health: viruses (HIV in particular).

Instructors : 

4 Instructors Rob Phillips, Eng & App. Sciences Pamela Bjorkman, Biology Office hours: After class; noon to 1PM Thursdays at the Broad Café or by appointment

Slide 5: 

5 Head TA: Dr. Jordan Schooler Office Hours: Mondays 12-1PM; Broad Café

Why HIV? : 

6 Why 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.

The Bi 1 homepage: : 

7 The Bi 1 homepage: http://www.its.caltech.edu/~bi1 Includes: A glossary Links to relevant websites Lecture notes, problem sets, course information

By the end of the course, students will gain a basic understanding of many issues affecting today’s world; e.g., : 

8 By the end of the course, students will gain a basic understanding of many issues affecting today’s world; e.g., Recombinant DNA technology, biotechnology Stem Cell Research Gene therapy Evolution Viral outbreaks (e.g., bird flu) Why biology needs physics and why physics needs biology Possible careers in fields that use biology

What we will NOT cover : 

9 What we will NOT cover Clinical aspects of AIDS and other viral diseases (we are not MDs!) Social/political issues surrounding HIV/AIDS

Clickers : 

10 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.

11 I am a Freshman Sophomore Junior Senior Other Clicker question:

12 My major is (or will probably be) Chemistry Math Physics (includes APh) Engineering Geology Biology Computer Science Other Clicker question:

13 I am glad to be taking Bi 1. Agree strongly Agree somewhat Disagree Disagree strongly and am very annoyed to have to take this course Clicker question:

14 I have had taken one or more Biology courses previously. A) YES B) NO Clicker question:

15 Which is correct? RNA --> DNA --> Protein Protein --> RNA --> DNA DNA --> RNA --> Protein DNA <--> RNA --> Protein Clicker question:

16 HIV and other viruses are susceptible to antibiotics. A) True B) False Clicker question:

Plagues and pestilence : 

17 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).

Fear/Ignorance about disease is nothing new… : 

18 Fear/Ignorance 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.

Slide 19: 

19 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? : 

20 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 See next two slides CD4 T cell count <200/µL What is CD4? What are T cells? (Lecture 20) Test positive for HIV What do HIV tests detect? (Lecture 12 plus problem sets/sections)

Figure 9-22 : 

21 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) : 

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

Slide 23: 

23 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 (more during lecture 29) HIV-2: related, less-prevalent than HIV-1 (is closely related to or identical to SIVsm) We will concentrate on Group M HIV-1 HIV 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)

Early history of HIV/AIDS : 

24 Early history of HIV/AIDS 1931 (1915-1941) -- Estimate for when SIVcpz (chimpanzee SIV) crossed into humans (mathematical modeling by Korber et al.; Los Alamos National Labs) 1959 -- Earliest known AIDS case: a Bantu man who lived near what is now Kinshasha, Republic of Congo (discovered in 1999 from analysis of old blood samples) 1981 -- first AIDS cases reported. Affected are homosexual males in US. (Pneumocystis carinii pneumonia and/or Kaposi’s sarcoma) 1982 -- AIDS cases in hemophiliacs, transfusion patients, IV drug users 1983 -- AIDS documented in US heterosexuals 1983 -- Majority of AIDS cases in Central Africa are heterosexuals 1983 -- Virus causing AIDS isolated by groups led by Luc Montagnier (France) and Robert Gallo (US), later named HIV (SARS virus isolated in 2 weeks in 2003 by international consortium of 13 labs) 1985 -- Blood test to detect HIV made available 1987 -- AZT licensed for use in AIDS patients 1996 -- anti-HIV drugs used in combination (HAART*) reduces death rates due to AIDS in developed countries *Highly Active Anti-Retroviral Therapy

Slide 25: 

25 10 leading causes of death in US in adults 25-44 years old

Slide 26: 

26 World-wide prevalence of HIV (May 2006) http://en.wikipedia.org/wiki/Image:HIV_Epidem.png

Consider Africa alone…. : 

27 Consider Africa alone…. 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.

Slide 28: 

28 Impact of AIDS on life expectancy in five African countries, 1970–2010 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 1980–1985 1985–1990 1990–1995 1995–2000 2000–2005 2005–2010 70 65 60 55 50 45 40 35 30 25 20 4.1

What is a virus? : 

29 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. Because viruses use host cell machinery to make their components (proteins, carbohydrates, membranes), they are harder to target with drugs than self-sufficient pathogens such as bacteria or fungi.

Slide 30: 

30 The genetic material in a virus can be DNA or RNA

Slide 31: 

31

Why don’t antibiotics work against viruses? : 

32 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.

Killing viruses : 

33 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)

Slide 34: 

34 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 : 

35 HIV is a RetrovirusRetroviruses do NOT follow the Central Dogma Retroviruses are 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)

Slide 36: 

36 Expression Membrane Targeting Budding Maturation Nuclear transport Integration Uncoating Reverse Transcription Binding Membrane Fusion Overview of Retroviral Life Cycle (For exogenous retrovirus start here) (For endogenous retrovirus start here)

Retroviral life cycle (Lectures 14-15) : 

37 Retroviral life cycle (Lectures 14-15) Retrovirus RNA is copied using viral Reverse Transcriptase (RT) into complementary strand of ssDNA (Replication, Lecture 9). ssDNA copied into dsDNA (in cytoplasm). Retroviral dsDNA migrates to host cell nucleus and is integrated (using viral integrase) into host cell DNA. Integrated viral DNA is now a PROVIRUS and infection is irreversible -- viral genes are now part of cell’s genome. RNA copies of proviral genes made by TRANSCRIPTION using host enzymes (Transcription, Lecture 10). Spliced RNA functions as mRNA -- is translated into viral proteins. Unspliced RNA strands are packaged into new viruses (Splicing, Lecture 10). You will understand this by the end of the course.

Some believe that HIV does not cause AIDS : 

38 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 AIDS : 

39 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.htmlA 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 : 

40 Koch’s 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.

Slide 41: 

41 If you drop the course, or if you register late, please email Patricia Mindorff mindorff@caltech.edu (in addition to the Registrar’s cards). Also, if you want to change sections, please email Patricia Mindorff mindorff@caltech.edu (don’t need an Add/Drop card -- just email Patricia) Patricia Mindorff works 9 AM - 5 PM, M-F

Slide 42: 

42 New AIDS cases and deaths due to AIDS have been reduced in the US

Figure 9-12 : 

43 Figure 9-12 Number of HIV cases worldwide at end of 2002

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