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Dendritic cells reveal a broad range of MHC class I epitopes for HIV-1 during ART

Dendritic cells reveal a broad range of MHC class I epitopes for HIV-1 during ART. Xiao-Li Huang, Zheng Fan, LuAnn Borowski , Robbie Mailliard , Morgane Rolland, James Mullins, Richard Day and Charles R. Rinaldo.

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Dendritic cells reveal a broad range of MHC class I epitopes for HIV-1 during ART

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  1. Dendritic cells reveal a broad range of MHC class I epitopes for HIV-1 during ART Xiao-Li Huang, ZhengFan, LuAnn Borowski, Robbie Mailliard, MorganeRolland, James Mullins, Richard Day and Charles R. Rinaldo

  2. Effects of ART on anti-HIV-1 T cell responses in chronic infection: Can DC immunotherapy control residual HIV-1? ART + DC Rx HIV ART Off ART HIV Anti-HIV-1 CTL • Previously shown that DC can increase the magnitude of anti-HIV-1 CD8+ T cell responses. • Can DC enhance the breadth of anti-HIV-1 CD8+ T cell responses during ART, particularly to Gag? Set point Set point Time

  3. CD4 CD8 NK CD8 Maturation of myeloid DC is essential for induction of antiviral T cell immunity Th1 polarization IL-1 IFNγ CD40L Afferent Pathway CD4 TNFα IL-12 IFNγ IL-2 CD40 dsRNA (Virus) Th1 TLR3 CD80 TCR CD86 MHC I - PEPTIDE IFNγ TNFα Mature DC Immature DC Antiviral reactivity Efferent Pathway

  4. DC enhance CD8+ T cell responses to HIV-1 proteome in subjects on ART SFC/106PBMC SFC/106PBMC (r = 0.845, P <0.001) SFC/106CD8+ T cells HLA A*0301,2501; B*2705,4402;Cw0202,0501; CD4 = 340, Viral load <50

  5. Potential epitopes revealed by DC DC enhance CD8+ T cell responses to Nef peptides in subjects on ART

  6. DC enhance CD8+ T cell responses to Nef peptides in subjects on ART • CD8+ T cells recognize more Nef peptides with DC than without DC (n=7) (P<0.001) • 21.6% (74/343) positive T cell responses with DC 1.5% (5/343) positive responses without DC • 2% (7/353) common responses with and without DC • DC enhanced the number of Nef peptide-responding T cells by 23.4-fold compared to T cells stimulated directly with peptides (P <0.001).

  7. Novel Nef epitope HLA B*2703 Nef76-84 LRPMTYKAA revealed by DC HLA A*0201,0301; B*2703,3701;Cw0602,1502; CD4 = 647, Viral load = 9,244

  8. NovelHLA B*2703 Nef76-84 LRPMTYKAA epitope revealed by DC Found in 34% of circulating HIV-1 subtype B sequences

  9. LRPMTYKAA LRPMTYKA RPMTYKAA LRPMTYKAAV PLRPMTYKAA EVGFPVRPQVPLRPM PVRPQVPLRPMTYK QVPLRPMTYKAAVDL RPMTYKAAVDLSHFL Polyfunctional CD8 T cell responses to novelHLA B*2703 Nef76-84LRPMTYKAA epitope induced by DC A 3 5 5 4 4 2 2 3 2 3 2 1 1 1 1 EVGFPVRPQVPLRPM PVRPQVPLRPMTYK QVPLRPMTYKAAVDL RPMTYKAAVDLSHFL 1.0 0.1 0.01 % of total CD8+ T cell response B 4 4 2 2 2 4 1 1 1 1 3 LRPMTYKAALRPMTYKA RPMTYKAA LRPMTYKAAV PLRPMTYKAA 1.0 0.1 0.01 % of total CD8+ T cell response

  10. Potential epitopes revealed by DC DC enhance CD8+ T cell responses to Gag peptides in subjects on ART

  11. DC enhance CD8+ T cell responses to Gag peptides in subjects on ART • CD8+ T cells recognize more Gag peptides with DC than without DC (n=7) (P<0.001) • 13.3% (114/854) positive T cell responses with DC 1.6% (14/854) positive responses without DC • 2.8% (24/854) commonresponses with and without DC • DC enhanced the number of Gag peptide-responding T cells by 8.5-fold compared to T cells stimulated directly with peptides (P <0.001).

  12. Novel Gag epitope HLA B*5101 p1722-31 RPGGKKKYKLrevealed by DC HLA A*0101,0201; B*5101,5701;Cw0602,0702; CD4 = 461, Viral load <50

  13. Novel Gag epitope HLA B*5101 p1722-31RPGGKKKYKL revealed by DC Found in 24% of circulating HIV-1 subtype B sequences

  14. PGGKKKYKL PGGKKKYK GGKKKYKL PGGKKKYKLK RPGGKKKYKL LDRWEKIRLRPGGKK EKIRLRPGGKKKYKL LRPGGKKKYKLKHIV GKKKYKLKHIVWASR Polyfunctional CD8 T cell responses to novelHLA B*5101 p1722-31 RPGGKKKYKLepitope induced by DC A 5 5 4 4 4 3 3 3 2 1 1 2 2 1 2 LDRWEKIRLRPGGKK EKIRLRPGGKKKYKL LRPGGKKKYKLKHIV GKKKYKLKHIVWASR 1.0 0.1 0.01 % of total CD8+ T cell response B 4 4 3 5 4 3 3 3 2 2 2 2 3 1 1 1 1 1 PGGKKKYKLPGGKKKYK GGKKKYKLPGGKKKYKLK RPGGKKKYKL 1.0 0.1 0.01 % of total CD8+ T cell response

  15. Conclusions • DC loaded with HIV-1 peptides induce greatest breadth of anti-HIV-1 memory recall, CD8+ T cell reactivity in persons on ART. • DC revealed T cell responses to 22% of 49 overlapping Nefpeptides compared to only 4% without DC. • DC revealed T cell responses to 16% of 122 overlapping Gag peptides compared to only 4% without DC. • DC reveal novel epitopes for Nef and Gag. • Breadth of memory recall, CD8+ T cell responses to HIV-1 epitopes during ARTas determined by conventional assays is significantly under-represented. • Supports use of DC in immunotherapy of HIV-1 infection.

  16. Acknowledgments • Multicenter AIDS Cohort Study (MACS): Volunteers and clinicians • University of Pittsburgh: Xiao-Li Huang, Zheng Fan, LuAnn Borowski, Weimin Jiang, Ping Zhang, Robbie Mailliard, Richard Day • University of Washington: Morgane Rolland, James Mullins • S. Ghanakar (BD PharMingen); M. Roederer (VRC/NIH) for SPICE • S. Bridges and R. Huebner (NIAID P01 AI-055794, U01 AI-35041, R37 AI-41870)

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