1 / 86

July 24th, 2008 HIV Lifecycle and Mechanisms of Antiretroviral Therapy David Spach, MD

July 24th, 2008 HIV Lifecycle and Mechanisms of Antiretroviral Therapy David Spach, MD.

amelia
Download Presentation

July 24th, 2008 HIV Lifecycle and Mechanisms of Antiretroviral Therapy David Spach, MD

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. July 24th, 2008 HIV Lifecycle and Mechanisms of Antiretroviral Therapy David Spach, MD

  2. HIV/AIDS 2008 Treatment UpdateAn In-Depth Look at the Viral Life Cycle to Understand Old and New Antiretroviral MedicationsDavid H. Spach, MDProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle DHS/PP

  3. HIV/AIDS 2008 Treatment Update • Overview of HIV Structure and Life Cycle • 2008 DHHS Antiretroviral Therapy Guidelines • Mechanisms of Action of Antiretroviral Medications DHS/PP

  4. HIV Structure and Life Cycle DHS/PP

  5. HIV: Basic Structure HIV RNA DHS/PP

  6. HIV: Basic Structure Envelope gp120 gp41 Nucleocapsid (p7) Capsid (p24) HIV RNA Matrix (p17) DHS/PP

  7. HIV: Functional Enzymes • What are the three key HIV enzymes involved in HIV replication? DHS/PP

  8. HIV Enzymes Reverse Transcriptase Integrase Protease DHS/PP

  9. Host (Human) Cell: Key HIV Receptors CD4 Receptor CCR5 Co-Receptor CXCR4 Co-Receptor Host Cell DHS/PP

  10. Question • What genetic alteration in human co-receptors is associated with relative resistance to HIV infection? DHS/PP

  11. CCR5-∆32 CCR5 CCR-∆32 Extracellular Space C C C C Host Cell Membrane Intracellular Space DHS/PP

  12. HIV: Life Cycle Nucleus CCR5 CD4 Host DNA HIV Host Cell

  13. HIV: Life Cycle Entry 3 Nucleus 2 CCR5 1 CD4 HIV Host Cell

  14. HIV: Life Cycle Uncoating Entry Nucleus CCR5 CD4 HIV RNA HIV Host Cell

  15. HIV: Life Cycle Uncoating Reverse Transcription Entry Nucleus CCR5 CD4 HIV RNA HIV DNA HIV Reverse Transcriptase Host Cell

  16. HIV: Life Cycle Uncoating Reverse Transcription Entry Integration Integrase Nucleus CCR5 CD4 HIV RNA HIV DNA HIV Proviral DNA HIV Host Cell

  17. HIV: Life Cycle Uncoating Reverse Transcription Transcription Entry Integration Nucleus CCR5 gRNA CD4 HIV RNA HIV DNA mRNA HIV Host Cell

  18. HIV: Life Cycle Uncoating Reverse Transcription Transcription Entry Integration Translation Nucleus CCR5 CD4 gp160 Protease HIV RNA HIV DNA mRNA HIV Myr Gag Host Cell Gag-Pol

  19. HIV: Life Cycle Uncoating Reverse Transcription Transcription Entry Integration Translation Assembly & Budding HIV Nucleus CCR5 CD4 HIV RNA HIV DNA mRNA HIV Myr Gag Host Cell Gag-Pol

  20. HIV: Life Cycle Entry Inhibitors Nucleoside RTI Integrase Inhibitors HIV Nucleus CCR5 CD4 HIV RNA HIV DNA mRNA HIV Protease Inhibitors Non-Nucleoside RTI Gag Host Cell Gag-Pol

  21. 2008 DHHS Antiretroviral Therapy Guidelines DHS/PP

  22. Case History • A 32-year-old HIV-infected woman returns to clinic to discuss starting antiretroviral therapy. Her CD4 count is 330 cells/m3 and her HIV RNA is 79,000 copies/ml. • According to the 2008 DHHS Antiretroviral Therapy Guidelines:- When should you start antiretroviral therapy on this patient? DHS/PP

  23. HIV: Natural History Acute HIV Year 1 DHS/PP

  24. Initiating Antiretroviral Therapy 500 350 200 Year 1 DHS/PP

  25. Initiating Antiretroviral TherapyJanuary 2008 DHHS Guidelines 500 Consider Antiretroviral Therapy 350 Initiate Antiretroviral Therapy Year 1 Source: DHHS Guidelines. www.aidsinfo.nih.gov DHS/PP

  26. Question • Why do you think we are more enthusiastic about starting antiretroviral therapy earlier now than 2-3 years ago? DHS/PP

  27. Rationale for Earlier Antiretroviral Therapy • More effective regimens • More convenient regimens • Less toxic regimens • Expanding data suggesting benefit of earlier therapy DHS/PP

  28. Case History • A 32-year-old HIV-infected woman returns to clinic to discuss starting antiretroviral therapy. Her CD4 count is 330 cells/m3 and her HIV RNA is 79,000 copies/ml. • According to the 2008 DHHS Antiretroviral Therapy Guidelines: - What regimen would you use? DHS/PP

  29. DHHS Panel: January 2008 ARV Therapy GuidelinesInitial Therapy: Preferred Regimens Construct Regimen by choosing one component from Column A and one component from Column B Column A Column B NNRTIEfavirenz PIAtazanavir + RitonavirFosamprenavir + Ritonavir BIDLopinavir/ritonavir (Kaletra) BID 2-NRTITenofovir/Emtricitabine(Truvada)Abacavir/Lamivudine(Epzicom): for patients who test negative for HLA-B5701 Picture Source: DHHS Guidelines. www.aidsinfo.nih.gov DHS/PP

  30. DHHS Panel: January 2008 ARV Therapy GuidelinesInitial Therapy: Alternative Regimens Construct Regimen by choosing one component from Column A and one component from Column B Column A Column B NNRTINevirapine PIAtazanavir (unboosted)Fosamprenavir (unboosted)Fosamprenavir + ritonavir qdLopinavir/ritonavir (Kaletra) qdSaquinavir + ritonavir 2-NRTIZidovudine/Lamivudine (Combivir)Didanosine + (Emtricitabine or Lamivudine) Picture Source: www.aidsinfo.nih.gov DHS/PP

  31. Case History • A 32-year-old HIV-infected woman returns to clinic to discuss starting antiretroviral therapy. Her CD4 count is 330 cells/m3 and her HIV RNA is 79,000 copies/ml. • According to the 2008 DHHS Antiretroviral Therapy Guidelines: - How should you ideally monitor after treatment is started? DHS/PP

  32. Antiretroviral Therapy: HIV RNA MonitoringOptimal Response: HIV RNA < 50 copies/ml Antiretroviral Therapy Started √ CD4 50 √ CD4 √ CD4 Goal: HIV RNA < 50 copies/ml 1 2 3 4 5 6 7 8 9 DHS/PP Time (Months)

  33. Entry Inhibitors DHS/PP

  34. HIV: Life Cycle HIV Entry Inhibitors Nucleus CCR5 CD4 HIV RNA HIV DNA mRNA HIV Myr Gag Host Cell Gag-Pol

  35. HIV: Basic Structure Envelope gp120 gp41 DHS/PP

  36. HIV: Envelope HIV gp41 gp120 CD4 Binding Groove V3 Region DHS/PP

  37. HIV: gp41 HIV gp41 DHS/PP

  38. Host Cellular ReceptorsCD4, CCR5, & CXCR4 Extracellular Space CCR5 CXCR4 CD4 Receptor Host Cell Membrane Intracellular Space DHS/PP

  39. HIV Cell Binding and Entry HIV gp120 CD4 Receptor CD4 Receptor Extracellular Space CCR5 Host Cell Membrane Intracellular Space DHS/PP

  40. HIV Cell Binding and Entry HIV CD4 Receptor Extracellular Space CCR5 Host Cell Membrane Intracellular Space DHS/PP

  41. HIV Cell Binding and Entry HIV CD4 Receptor V3 Region Extracellular Space CCR5 Host Cell Membrane Intracellular Space DHS/PP

  42. HIV Cell Binding and Entry HIV CD4 Receptor Extracellular Space CCR5 Host Cell Membrane Intracellular Space DHS/PP

  43. HIV Cell Binding and Entry HIV gp41 CD4 Receptor Extracellular Space CCR5 Host Cell Membrane Intracellular Space DHS/PP

  44. HIV Cell Binding and Entry HIV gp41 Extracellular Space Host Cell Membrane Intracellular Space DHS/PP

  45. HIV Cell Binding and Entry HIV Heptad Repeat 2 [HR2] HR2 gp41 HR1 Heptad Repeat 1 [HR1] Extracellular Space Host Cell Membrane Intracellular Space DHS/PP

  46. HIV Cell Binding and Entry HIV Extracellular Space Host Cell Membrane Intracellular Space DHS/PP

  47. HIV Cell Binding and Entry HIV HIV Membrane Host Cell Membrane DHS/PP

  48. HIV Cell Binding and Entry HIV HIV Membrane Host Cell Membrane DHS/PP

  49. R5-Tropic Virus: Binds to CCR5 R5-Tropic HIV V3 Region CD4 Receptor CD4 Receptor Extracellular Space CXCR4 CCR5 Host Cell Membrane Intracellular Space DHS/PP

  50. X4-Tropic Virus: Binds to CXCR4 X4-Tropic HIV V3 Region CD4 Receptor CD4 Receptor Extracellular Space CXCR4 CCR5 Host Cell Membrane Intracellular Space DHS/PP

More Related