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The role of immune responses in HIV-1 Infection

The role of immune responses in HIV-1 Infection. Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School Boston, MA USA. Natural History of HIV-1. symptoms. 1000. 10 6. CD4. 800. 10 5. HIV RNA copies/ml. HIV RNA. 600. VZV TB

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The role of immune responses in HIV-1 Infection

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  1. The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School Boston, MA USA

  2. Natural History of HIV-1 symptoms 1000 106 CD4 800 105 HIV RNA copies/ml HIV RNA 600 VZV TB Kaposi Sarcoma CD4 per mm3 104 400 200 PCP CMV MAC Crypto Lymphoma 1 5 10 15 • Time (years)

  3. One year The level of HIV in the blood stream predicts subsequent survival Rapid Progression RNA particles/ml plasma Viral set point Slow Progression

  4. What influences viral load in HIV infection?

  5. Viruses are not able to reproduce on their own

  6. New virus assembly 2-3 Days

  7. Viral set point is determined by number of viruses produced by infected cells

  8. Potential factors influencing the viral set point Attenuated virus Host immune response Host genetic factors

  9. Potential factors influencing the viral set point Attenuated virus Host immune response Host genetic factors HAART

  10. New virus assembly 2-3 Days Example: Sidney blood bank cohort Virus had a “mistake” in the nef gene Attenuated viruses

  11. Host genetic factors Attenuated viruses

  12. Co-receptor polymorphisms can prevent entry of virus into cells 32 base pair deletion in CCR5 CD4 CCR5

  13. Some molecules on the cell of an individual are associated with improved viral control and slow disease progression B27 B57 Migueles, PNAS 97:2709, 2000

  14. Host genetic factors Attenuated viruses Host immune responses

  15. B cell New virus assembly Humoral Immune System: Neutralizing Antibodies

  16. Soluble factors CTL New virus assembly Cellular immune system: Killer T cells Cytotoxic T cell

  17. CTL B cell New virus assembly Th Th Soluble factors

  18. Th B cell CTL Th

  19. The Generals (T helper cells trained to target HIV)

  20. Enemy Infected cell Infantry (CTL) Generals (T Helper cells)

  21. Why are the generals absent in most infected persons?

  22. Enemy Infected cell Infantry (CTL) Generals (T Helper cells)

  23. Virus-Specific T Helper Cells:Essential for Maintenance of Effective CTL Viremia CTL Relative magnitude Viremia CTL Th cells present Th cells absent

  24. Is there any way to enhance the immune response against HIV?

  25. Enemy (Infected cells) Infantry (CTL) Generals (T helper cells)

  26. HAART Enemy (Infected cell) Infantry (CTL) Generals (T Helper cells)

  27. Effect of Early Treatment on the Generals (HIV-Specific T Helper Cells) 1000 100 Magnitude of Helper Cells 10 1 0 20 40 60 80 Weeks on Treatment

  28. What happens if you stop treatment?

  29. HAART Early treatment of acute HIV infection followed by treatment interruption 160000 120000 viral load (copies RNA/mL) 80000 40000 0 0 5 10 15 20 25 30 35 40 Weeks after first treatment interruption

  30. Very early treatment with HAART leads to enhanced natural control of HIV

  31. Where else do we find evidence for immune control in AIDS virus infection ? • In monkey studies, removing killer cells led to dramatic increases in viral load and restoring Killer T cells in those same monkey studies led to suppression of viral load • Individuals with high levels of Killer T cells have been shown to have low viral loads • Two interesting groups of individuals • HIV-1 long-term nonprogressors (LTNP) • HIV-1 exposed, but uninfected individuals (HEPS)

  32. LTNP • Infected 21 years • Normal T cells • Undetectable viral load • Never on anti-HIV meds LTNP have strong and broadly directed killer cell responses and helper cell responses

  33. HEPS • Most well known: • Nairobi sex worker cohort (Rowland-Jones et al.) • Found killer T cell responses in these HEPS, that may contribute to protection from HIV • Our group: collaboration with Lusaka, Zambia (PI: Susan Allen) studying killer cells in discordant couples and their partners Poster session Thursday 12-2 pm (Addo)

  34. Based on these pieces of data, it is felt that an effective HIV-1 vaccine needs to elicit cellular immune responses, in particular Killer T cell responses +/- Helper T cell responses Most recent and compelling data derive from monkey studies demonstrating that Killer T cell have an impact on vaccine efficacy in this setting (Robbinson, Barouch/Letvin, Shiver) Many vaccine approaches/trials currently in study Vaccine development

  35. Our current Research • Understanding of total the killer T cell and helper cell response against HIV, not only to single proteins like previous studies. • Analysis of the virus by sequencing Bruce Walker morning Tuesday plenary Addo A05 Tuesday 14-15:30

  36. More research needed for other virus types and other ethnicities • Durban, RSA • Immune responses in Clade C-Infection • Mother to child transmission and pediatric treatment and treatment interruption studies • NIH contract Epitope mapping in Non-Caucasians

  37. Lab Nelson Mandela School of Medicine University of Natal

  38. Why is HIV not controlled by the immune system like other chronic viral infections? Mono Chicken pox Herpes simplex

  39. Problems • VIRAL ESCAPE • VIRAL DIVERSITY

  40. How HIV mutates to escape Killer T-cells

  41. Viral escape Examples: • Goulder et al, Nature 2001 • Viral escape mutants can be transmitted from mother to child • Barouch et al, Nature 2002 • Loss of viral control in a vaccinated animal associated with viral escape in one epitope

  42. Viral DiversityComparing Viruses:How much does HIV evolve compared to Flu? More Variation Less Variation

  43. 1997-1998 Canadian Flu 1996 Global Flu Influenza variation compared to HIV variation

  44. 1997-1998 Canadian Flu 1996 Global Flu Influenza variation compared to HIV variation 1990-1991 Amsterdam 1997 Dem Rep of Congo

  45. The extreme variability of HIV over time is a major impediment to immune control, effective drug therapy and vaccine development

  46. Acknowledgements • Marcus Altfeld • Xu Yu • Almas Rathod • Cecily Fitzpatrick • Paul Lee • Philip Goulder • Christian Brander • Eric Rosenberg • Bruce Walker Funding Sources: German Research Council (DFG) amfAR Concerned Parents for AIDS Research (CPFA)

  47. HLA-B27 is associated with slow progression to AIDS 106 105 Viral Load 104 n = 10 HLA-B27+ 103 102

  48. The dominant CTL response in HLA-B27+ individuals: HIV Gag p24 KK10 epitope K I L G L W I L R K HLA B27 molecule

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