HIV

1. HIV/AIDS: A World Epidemic www.avert.org

2. HIV vs. AIDS HIV 1. Human Immunodeficieny Virus 2. Two types: HIV-1 and HIV-2 3. Retrovirus 4. Lentivirus- “slow” virus AIDS 1. Acquired Immune Deficiency Syndrome 2. Last and most severe stage of HIV

3. HIV-1 and HIV-2 Have 9 genes each Linked with same infectious diseases HIV-2 develops slower and more mild HIV-2 less infectious at beginning of disease HIV-2 infectiousness increases faster for short period Have different geographical locations -HIV-2 is primarily in West Africa

4. How is HIV Transmitted? Unprotected sexual contact Blood transfusions Drug substance abuse Bodily fluids -e.g. semen, breast milk, blood, vaginal fluid

5. History of AIDS AIDS originated in central Africa from monkeys STLV-III mutated into HTLV-III and spread to humans by liver transplant Not detected in humans until an increase in Kaposi’s cancer was discovered

6. Kaposi’s Sarcoma Cancerous lesions Caused by overgrowth of blood vessels Defines AIDS Found in skin, oral cavity, lymph nodes, lungs, and intestines May be caused by Kaposi’s sarcoma herpes virus

7. Structure of HIV Viral envelope -outer layer and made up of two lipid layers from host cell Viral core -inside the envelope -bullet shaped capsid that contains 2 strands of RNA (9 genes each) -has 3 enzymes-reverse transcriptase, integrase, and protease

8. Structure of HIV

9. HIV Life Cycle Attachment or entry of the cell Reverse transcription and DNA synthesis Integration Transcription Translation Assembly and budding

10. Attachment or Entry Into the Cell gp120 molecules attach to CD4 molecules on the cell’s surface virus’s membrane and the CD4+ cell fuse together After they fuse, the virus releases its RNA, proteins, and enzymes into the cell

11. Reverse Transcription and DNA Synthesis Viral RNA is converted to DNA by reverse transcriptase HIV DNA transported from the cytoplasm to the nucleus

12. Integration HIV integrase-makes HIV DNA part of the host cell’s DNA Now called a provirus

13. Transcription mRNA produced by the host cell Viral genes control transcription (tat gene) After transcription, mRNA is transferred from the nucleus to the cytoplasm (rev genes)

14. Translation Rev gene essential in this process The virus takes over the host cell’s ribosomes Uses ribosomes to make new viral proteins and enzymes

15. Assembly and Budding HIV proteins, enzymes, and RNA assemble inside the cell’s membrane Viral particles bud off the host cell Viral particle takes part of the host cell’s membrane -becomes virus’s envelope Virus not contagious (immature)

16. Protease Enzyme Cuts the HIV proteins and enzymes into small pieces Virus becomes infectious (mature) Virus can be released from the cell

17. Latent vs. Productive Latent infections 1. long duration between the initial infection and the start of symptoms 2. small production of viral proteins 3. viral genome is an integrated provirus Productive infections 1. A large number of viral replication 2. The release of infectious viruses 3. Causes cell death 4. Spreads the virus to other cells

18. How does HIV weaken the immune system? HIV attacks CD4+ T cells 1.Main HIV target 2.T-helper cells 3.Defend body against pathogens 4.Detect signals in the body 5.Send B cells messages to make antibodies

19. How does HIV weaken the immune system? HIV also attacks CD8+ cells (T-8 cells) 1.Two forms a. Killer T cells-kill infected cells b.Suppressor T cells-shut down immune response 2. Release lymphokines to end the attack

20. So how does HIV weaken the immune system? Immune response is dysfunctional CD4+ cells are inefficient Build-up of lymphokines HIV cells keep replicating

21. Stages of HIV HIV can remain dormant in the body for many years Primary phase -viral genome enters and takes over the cell -T-4 cell count drops 20-40% High mutation rate during replication activates the latent virus

22. AIDS: The final stage of HIV Normal CD4+cell count- 500-1,500 cells per micro liter AIDS-when CD4+ T cells fall below 200 cells per micro liter Most severe stage of HIV

23. Microorganisms Common in all people Causes severe infection and even death in AIDS patients Increase HIV replication

24. Microbes that cause death in AIDS patients Mycobacterium genavense Mycobacterium avium-intercellulare Mycobacterium tuberculosis Pneumocystis carinii Cytomegalovirus

25. Mycobacterium genavense Recently discovered species of acid-fast rod mycobacteria Detected through blood culture bottles -does not grow on solid media Resides in the gut and spreads to liver, lymph nodes, lungs, and spleen Symptoms of diarrhea, fever, and substantial weight loss Suffer from a very low CD4+ cell count No treatment effect

26. Mycobacterium avium-intercellulare Similar to Mycobacterium genavense Speeds up the development HIV Occur in any bodily organs in those with HIV with CD4+ cell count below 100 cells/microliter Symptoms- weight loss, diarrhea, fever, anemia, and growth of the liver and spleen

27. Mycobacterium tuberculosis Airborne disease -easily spread between people Dormant in healthy people -when activated causes TB HIV people are at a greater risk of getting TB and dying from it -primary cause of death in people with HIV Increases HIV replication

28. Pneumocystis carinii Opportunistic pathogen Recently discovered to be a fungus Causes most cases of infection -pneumonia -3/4’s of those with HIV will get it, if not treated -reactivation of a dormant infection from childhood TMP-SMX is the drug to treat it

29. Cytomegalovirus Not well-known Rarely causes infection in healthy people May not be fought off by immune system, but is inactivated Causes mononucleosis disease if activated In HIV-positive people: -can cause severe illness, such as pneumonia, hepatitis, and brain inflammation

30. HIV Treatment Drugs that stop viral replication or entry into the cell are used There are 20 approved antiretroviral drugs Antiretroviral drugs interfere with HIV enzymes Divided into 3 categories: 1. Reverse transcriptase inhibitors (RT) 2. Protease inhibitors (PT) 3. Fusion inhibitors (FI)

31. Reverse Transcriptase Inhibitors Inhibit reverse transcriptase enzyme The virus can no longer replicate Function better in macrophages than in lymphocytes Ineffective after integration Two types: 1. Nucleoside/nucleotide inhibitors 2. Non-nucleoside inhibitors

32. Types of RT Nucleoside/nucleotide inhibitors: -provide defective nucleotides interfering with DNA replication Non-nucleoside inhibitors: -stop replication by binding to the reverse transcriptase enzyme

33. Protease Inhibitors More effective than other inhibitors -works at later stage of life cycle Blocks function of protease Administered to patients who have an elevated level of the virus in the body On October 20, 2003, a new protease inhibitor drug was approved by the FDA, called LEXIVA.

34. Fusion inhibitors New class of drugs Obstruct the virus’s capability to bind with and enter the host cell -alters the cell’s protein envelope

35. Highly Active AntiretroviralTherapy Prolong life of HIV patients They are not a cure for AIDS Combination of RT and PT inhibitors Cause serious side effects -e.g muscle wasting and heart failure

36. Drug Therapy Not completely effective in treating HIV -virus resides in reservoirs in the body Two main types of reservoirs: 1.CD4+ lymphocytes 2. Macrophages

37. Current Research Engineered virus AIDSVAX Hepatitis G virus Four new classes of antiretroviral drugs

38. Engineered Virus Have revealed a 1000-fold decline in HIV viral load A decline of 92% of HIV-1 load Revival rate of 17% in CD4+ T cells Does not eliminate the virus completely Not toxic, has no bad side effects, and the virus can not become resistant Stays in the body; no need to reintroduce it

39. AIDSVAX Made up of 120 outer envelope proteins found on two HIV strains Vaccine is being studied in Thailand The first vaccine to reach phase III of the testing process

40. Hepatitis G Virus Does not cause disease Beneficial to those infected with HIV Found to stop HIV replication Likeliness of an earlier death increases with the loss of GBV-C RNA

41. Four New Classes of Drugs 1. Entry Inhibitors: - prevent the HIV virus from entering the host cell 2. Integrase Inhibitors: -Prevent the ability of HIV to introduce its genes into the host cell’s DNA 3. Assembly and budding inhibitor drugs: -get in the way of the HIV’s final life cycle stage 4. Cellular metabolism modulators: -obstruct the cellular processes that are required for HIV to replicate

42. Further Research Suggestions Possibly transport certain toxins to destroy the infected macrophages A study should be conducted to determine the optimal time of therapy administration An experiment should be done to determine when to halt drug therapy and when to reintroduce them in order to reduce severe side effects

43. “Better Safe than Sorry”