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Immune Control of Clade C HIV Infection

Immune Control of Clade C HIV Infection. Bruce D Walker, MD University of KwaZulu Natal Ragon Institute of MGH, Harvard and MIT. Question. Why do children do worse than adults when they become HIV infected? Can answering this question shed light on important immune mechanisms?.

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Immune Control of Clade C HIV Infection

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  1. Immune Control of Clade C HIV Infection Bruce D Walker, MD University of KwaZulu Natal Ragon Institute of MGH, Harvard and MIT

  2. Question • Why do children do worse than adults when they become HIV infected? • Can answering this question shed light on important immune mechanisms?

  3. HIV Prevalence in Antenatal Clinics: 2001

  4. Philip Goulder Photini Kiepiela Not shown: H. Coovadia S. Abdool Karim

  5. Doris Duke Medical Research Institute UKZN

  6. DDMRI

  7. Mark Schwartz

  8. Kaye Ajao Krista Dong

  9. Thumbi Ndung’u

  10. CTL Can we find signals indicating what is involved in immune control?

  11. CTL Host Immune Responses Virus Host Genetics

  12. CTL Host Genetics

  13. HLA Class I 817 B alleles 263 C alleles 486 A alleles

  14. Experimental Design • Subjects • HIV-infected Zulu/Xhosa (n=706) • Methods • High resolution HLA typing • Viral load determination

  15. HLA B-association with control of HIV 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 B*57 p < 0.0001 p = 0.0014 p = 0.0006 B*8101 B*5801 B*5802 B*1801 p < 0.0001 Kiepiela et al, Nature, 2004 p = 0.0008

  16. HLA-association with control of HIV 2.0 2.5 3.0 3.5 4.5 5.0 5.5 6.0 4.0 p = 0.0006 B*5801 B*5802 p < 0.0001 Kiepiela et al, Nature, 2004

  17. Marked differences in HLA associations: B*5801 and B*5802 p< 0.0001 10000000 1000000 100000 Viral load (RNA Copies/ml) 10000 Median Median Median 1000 = 75, 200 = 33, 000 = 14, 650 100 10 B5801 B5802 Neither - n = 93 n = 259 n = 722 Ngumbela et al, ARHR 2008

  18. Marked differences in HLA associations: B*5801 and B*5802 p< 0.0001 p< 0.0001 10000000 1000000 100000 Viral load (RNA Copies/ml) 10000 Median Median Median 1000 = 75, 200 = 33, 000 = 14, 650 100 10 Neither B5801 B5802 n = 93 n = 259 n = 722 Ngumbela et al, ARHR 2008

  19. HLA B*5802 is deleterious?

  20. Conclusions I • HLA B alleles influence viral load • Certain alleles are associated with protection, and others with progression

  21. CTL How do HLA alleles influence viral load?

  22. B Pocket F Pocket HLA Class I Infected cell

  23. Viral Peptide B Pocket F Pocket HLA Class I Infected cell

  24. T Cell Receptor B Pocket F Pocket HLA Class I Infected cell

  25. Experimental Design • Subjects • HIV infected treatment naïve Zulu/Xhosa • Methods • Determine the dominant protein targeted by CD8 T cells by ICS using pooled peptides (61 subjects) • Determine breadth of CD8 T cell responses by Elispot, using individual overlapping peptides spanning all HIV proteins (578 subjects) • Correlate to viral load

  26. A dominant CD8 Gag-specific response is associated with lower viremia Ramduth, Chetty, Mngquandaniso et al, JID 2005

  27. The breadth of the Gag-specific CD8 response is associated with lower viral load 94,000 21,000 Kiepiela, Leslie, Honeyborne et al, Nature Medicine 2007

  28. The breadth of the Env-specific CD8 response is associated with higher viral load 220,000 29,000 Kiepiela, Leslie, Honeyborne et al, Nature Medicine 2007

  29. HLA-association with control of HIV 2.0 2.5 3.0 3.5 4.5 5.0 5.5 6.0 4.0 p = 0.0006 B*5801 B*5802 p < 0.0001 Kiepiela et al, Nature, 2004

  30. Gag-specific CD8 responses are minimal to undetectable in the first 6 months after vertical transmission Thobakgale et al, JV 2007

  31. Are there functional differences in HIV-specific immune responses?

  32. Experimental Design • Subjects selected from a cohort of 288 persons with chronic HIV infection • 13 high Gag-specific CD8 T cell responses • Mean breadth 8+2.6 • Mean magnitude 3380+1304 SFC/10^6 PBMC • 13 low Gag-specific CD8 T cell responses • Mean breadth 0.64+0.6 • Mean magnitude 808.8+1038 SFC/106 PBMC

  33. Subjects matched for CD4 count and overall Elispot responses No difference in terms of CD4 cell counts or total elispot responses in high vs low Gag responders Julg, Williams, Reddy et al, unpublished

  34. Experimental Design • Methods • Measure the ability of freshly isolated CD8 T cells to • Inhibit a heterologous strain of virus in autologous CD4 cells • Proliferate in response to HIV peptides • Secrete cytokines in response to HIV peptides

  35. High Gag responders have significantly lower viral loads Julg, Williams, Reddy et al, unpublished

  36. 1000000 100000 10000 CD4 uninfected CD4 infected with p24 pg/ml 1000 HIV-1 (X4) MOI 0.1 100 10 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Day

  37. 1000000 100000 10000 CD4 uninfected CD4 infected with p24 pg/ml 1000 HIV-1 (X4) MOI 0.1 100 CD8 Cells added 10 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Day Julg, Williams, Reddy et al, unpublished

  38. High Gag-responders inhibit virus replication better Julg, Williams, Reddy et al, unpublished

  39. Conclusions II • Broader Gag-specific CD8 T cell responses are associated with lower viral loads • Broader Env-specific CD8 T cell responses are associated with higher viral loads • Broad Gag-specific CD8 T cell responses are associated with enhanced ability to neutralize infectious HIV and greater functionality

  40. CTL Virus

  41. CTL Viral Epitope

  42. W S HLA B5801

  43. Rapid selection for mutation in the B5801- restricted TW10 epitope TSTLQEQIAW Wild type T242N --N-------

  44. Figure1 % viral variant % viral variant Days post-infection Days post-infection Log viral load % GFP+ cells Age (days) Wild-type virus outgrows mutant T242N % viral variant % viral variant days post infection Martinez-Picado, J Virol, 2006

  45. Number of HLA-B-associated Gag mutations correlated with median viral load for each allele B*4901 B*51 B*41 B*4202 100000 B*0705 B*1801 r = -0.56 50000 B*1402 B*5802 p = 0.0034 B*1510 B*0801 B*1503 Viral Load B*3501 B*4501 B*0702 B*4201 B*4403 B*3910 B*1302 B*1401 B*5301 B*5801 B*5702 B*1516 B*8101 10000 B*5703 Matthews, Prendergast et al, J Virol, 2008 0 1 2 3 4 5 6 Number of HLA-B Gag mutations

  46. Conclusions III • Gag-specific CD8 T cell responses select for fitness mutants that cripple HIV

  47. CTL What is this epitope-specific immune pressure doing at a population level?

  48. Global CTL Escape Collaboration • Subjects • 2800 persons with chronic HIV infection • 9 cohorts, 5 continents • Methods • HLA typing • Virus sequencing in Gag • Analyze the relationship between HLA prevalence and detection of escape mutations Y Kawashima et al, Nature 2009

  49. Percent escape mutant in the entire population Y Kawashima et al, Nature in press

  50. Percent escape mutant in persons NOT expressing HLA B51 Y Kawashima et al, Nature in press

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