COH603: Public Health Biology

1. Class 3: Monday, June 10 2013 COH603: Public Health Biology

2. Infectious Disease • Monday • HIV/AIDS • TB • Wednesday (not on Midterm) • HPV • Malaria • http://www.niaid.nih.gov • http://www.cdc.gov • http://www.who.int/en/

3. HIV/AIDS • HIV belongs to a class of viruses known as retroviruses. • Retroviruses are viruses that contain RNA (ribonucleic acid) as their genetic material. • HIV uses an enzyme called reverse transcriptase to convert its RNA into DNA (deoxyribonucleic acid) and then proceeds to replicate itself using the cell's machinery.

4. The Biology of HIV • HIV belongs to a subgroup known as lentiviruses, or "slow" viruses. • Lentivirusesare known for having a long time period between initial infection and the beginning of serious symptoms.

5. HIV Structure

6. The Viral Envelope • HIV is spherical in shape and has a diameter of 1/10,000 of a millimeter. • Composed of bilayer lipid membrane • Membrane proteins from the host cell, as well as 72 copies (on average) of a complex HIV protein known as Env. • Envconsists of three molecules, glycoprotein 120 (gp120), and three molecules, gyclycoprotein41 (gp41)

7. The Viral Core • made up of 2,000 copies of the viral protein, p24. • Two single strands of HIV RNA, each of which has a complete copy of the virus's genes. • HIV has three structural genes (gag, pol, and env) • information needed to make structural proteins for new virus particles.

8. Additional Viral Genes • HIV has six regulatory genes (tat, rev, nef, vif, vpr, and vpu) • contain information needed to produce proteins that control the ability of HIV to infect a cell, produce new copies of virus, or cause disease.

9. Additional Viral Proteins • P7, the HIV nucleocapsid protein. • Three enzymes carry out later steps in the virus's life cycle: • Reverse transcriptase • Integrase • Protease.

11. HIV Evades the Immune Response • Reverse transcriptaseoften makes random mistakes. • New types or strains of HIV develop in a person infected with HIV. • Evolution of HIV strains selects for those most successful at rapid infection and immune evasion • Its ability to evolve rapidly is one of the major reasons why HIV is such a deadly virus.

12. Bacterial and Viral Evolution • HIV replicates produces a genetically heterogenous population A plate of bacteria

13. Bacterial and Viral Evolution • The bacterial population experiences a selective pressure against it – an environment A plate of bacteria + “environment

14. Bacterial and Viral Evolution • The bacterial population experiences a selective pressure against it – an antibiotic A plate of bacteria + antibiotic

15. Bacterial and Viral Evolution • The new environment favors the growth of those bacteria who are resistant (selection) A plate of bacteria + antibiotic

16. Bacterial and Viral Evolution • Over generations of use, the population has evolved and become resistant

17. HIV Destorys the Immune System • Brief Intro in the Immune System

18. Lymphocytes • T cells and B cells protect against antigens • Anything body perceives as foreign such as bacteria and bacterial toxins, viruses, mismatched RBCs, cancer cells

19. B and T cells • T cells • Manage immune response • Attack and destroy infected cells • B cells • Produce plasma cells, which secrete antibodies • Antibodies mark antigens for destruction by phagocytosis or other means

20. Surface barriers • Skin • Mucous membranes Innate defenses Internal defenses • Phagocytes • Natural killer cells • Inflammation • Antimicrobial proteins • Fever Humoral immunity • B cells Adaptive defenses Cellular immunity • T cells

21. Two Parts to Adaptive Defense • Humoral Immunity • Antibodies, produced by lymphocytes, circulating freely in body fluids • Cell-mediated immunity • Lymphocytes act against target cell • Directly – by killing infected cells • Indirectly – by releasing chemicals

22. Cells of the Adaptive Immunity • Three types of cells • Two types of lymphocytes • B lymphocytes (B cells)—humoral immunity • T lymphocytes (T cells)—cellular immunity • Antigen-presenting cells (APCs) • Do not respond to specific antigens • Play essential auxiliary roles in immunity

23. Humoral immunity Adaptive defenses Antigen Primary response (initial encounter with antigen) Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with noncomplementary receptors remain inactive) Proliferation to form a clone Activated B cells Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secreted antibody molecules

24. Secondary immune response to antigen A is faster and larger; primary immune response to antigen B is similar to that for antigen A. Primary immune response to antigen A occurs after a delay. 104 103 Antibody titer (antibody concentration) in plasma (arbitrary units) 102 101 Anti- Bodies to B Anti- Bodies to A 100 0 28 35 42 49 56 7 14 21 Second exposure to antigen A; first exposure to antigen B First exposure to antigen A Time (days)

25. Cell-Mediated Response • T cells provide defense against intracellular antigens • Some T cells directly kill cells; others release chemicals that regulate immune response

26. Cellular immunity Adaptive defenses Immature lymphocyte Red bone marrow T cell receptor T cell receptor Maturation Class I MHC protein displaying antigen Class II MHC protein displaying antigen CD8 cell CD4 cell Thymus Activation Activation APC (dendritic cell) Memory cells APC (dendritic cell) CD4 CD8 CD4 cells become either helper T cells or regulatory T cells Lymphoid tissues and organs CD8 cells become cytotoxic T cells Effector cells Blood plasma

27. T cell populations • Two populations of T cells based on which glycoprotein surface receptors displayed • CD4 cells • CD8 cells • Naive T cells simply termed CD4 or CD8 cells

28. Activated CD4 T cells • CD4 cells usually become helper T cells (TH) • activate B cells, other T cells, macrophages, and direct adaptive immune response • Some become regulatory T cells – moderate immune response • Can also become memory T cells

29. Activated CD8 T Cells • CD8 cells become cytotoxic T cells (TC) • Destroy cells harboring foreign antigens • Also become memory T cells

30. HIV and the Immune System • HIV destroys billions of CD4+ T cells in a person infected with HIV, eventually overwhelming the immune system's capacity to regenerate or fight other infections.

31. Cell Death – Lytic Activity • CD4+ T cells may be killed when a large amount of virus is produced and buds out from the cell surface. The budding process disrupts the cell membrane and causes the cell to die.

32. Cell Death - Apoptosis • The cell can also expire when the virus excessively uses the cell’s machinery for its own purposes, disrupting normal activities needed for the survival of the cell. • Programmed cell death

33. Cell Death - Immune Response • CD4+ T cells infected cells show signs of stress that activates CD8+ T cells to produce cytotoxic effects • Granzyme B • Perforin

34. Additional Effects • Studies suggest that HIV also destroys precursor cells • HIV can also damage the bone marrow and the thymus, which are needed for developing precursor cells. • The bone marrow and thymus lose their ability to regenerate, further compounding the suppression of the immune system.

35. Hematopoietic stem cell (hemocytoblast) Stem cells Lymphoid stem cell Myeloid stem cell Committed cells Myeloblast T lymphocyte precursor Myeloblast Myeloblast Monoblast B lymphocyte precursor Developmental pathway Promyelocyte Promyelocyte Promyelocyte Promonocyte Basophilic myelocyte Eosinophilic myelocyte Neutrophilic myelocyte Neutrophilic band cells Eosinophilic band cells Basophilic band cells Agranular leukocytes Granular leukocytes Monocytes Eosinophils Basophils Neutrophils B lymphocytes T lymphocytes (a) (b) (c) (d) (e) (f) Some become Some become Some become Macrophages (tissues) Plasma cells Effector T cells

36. HIV Evades Immune Response • The virus can hide within the cytoplasm or integrate into the cell’s genetic material (chromosomes). • Shielded from the immune system, HIV can lie dormant in an infected cell for months or even years. • Anti-RV drugs will not affect dormant virus

37. Clinical Progression of HIV

38. Acute Primary Infection • Virus infects a large number of CD4+ T cells and replicates rapidly. • The blood has a high number of HIV copies (viral load) • spread throughout the body, seeding organs (thymus, spleen, and lymph nodes) • The virus may integrate and hide in the cell’s genetic material. • The virus lies dormant for an extended period of time. • Up to 70 percent of HIV-infected people suffer flu-like symptoms.

39. Clinical Latency • Aperson infected with HIV may remain free of HIV-related symptoms for several years despite the fact that HIV continues to replicate in the lymphoid organs where it initially seeded.

40. Constitutional Symptoms of AIDS • More than 50 percent of people with the human immunodeficiency virus, or HIV, report experiencing constitutional symptoms, which are symptoms that affect the entire body • Night Sweats • Fever • Weight Loss • Fatigue

41. Progression to AIDS • The immune system eventually deteriorates to the point that the human body is unable to fight off other infections. • Viral load in the blood dramatically increases while CD4+ T cells drops to low levels. • An HIV-infected person is diagnosed with AIDS when he or she has one or more opportunistic infections, such as pneumonia or tuberculosis, and has fewer than 200 CD4+ T cells per cubic millimeter of blood.

42. Factors that Influence Progression • People infected with HIV who have specific genetic mutations in one of their two copies of the CCR5 gene progress to AIDS slower than people with two normal copies of the CCR5 gene. • Rare percentage with two mutant copies of the CCR5 gene who appearto be protected from HIV infection. • Gene mutations in other HIV co-receptors such as CXCR4 also may influence the rate of disease progression.

43. Viral Load • The amount of HIV in a person’s blood often is called his or her viral load. • People with high viral loads are more likely to progress to AIDS faster than people with lower levels of the virus. • The level of HIV in a person’s blood after the first few months of infection, known as the viral set point, also influences the speed of progression to AIDS. • Those with higher viral set point are much more likely to get sick faster than those with lower viral set point.

44. Viral Load and HAART • Highly active antiretroviral therapy (HAART), acombination of three or more antiretroviral drugs, can help lower the viral load and viral set point for those infected with HIV. • Viral Load is the determining factor for person-to-person viral transmission