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Erika Castro, MD, PhD Laboratory of AIDS Immunopathogenesis Division of Immunology and Allergy

Cross-clade recognition of Gag-p24 GPSHKARVL epitope restricted by HLA-B7 in a HIV-1 CRF15_01B infected individual. Erika Castro, MD, PhD Laboratory of AIDS Immunopathogenesis Division of Immunology and Allergy Lausanne University Hospital Switzerland.

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Erika Castro, MD, PhD Laboratory of AIDS Immunopathogenesis Division of Immunology and Allergy

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  1. Cross-clade recognition of Gag-p24 GPSHKARVL epitope restricted by HLA-B7 in a HIV-1 CRF15_01B infected individual Erika Castro, MD, PhD Laboratory of AIDS Immunopathogenesis Division of Immunology and Allergy Lausanne University Hospital Switzerland

  2. Cross-clade epitopes are relevant tools in vaccine development CD8 and CD4 T-cell epitopes databases relay on B sequences Sequence database, Los Alamos, National Laboratory Subtype distribution of collected HIV-1 sequences Most new infections arise in non-B and circulating recombinant forms “CRFs” epidemic’s burden

  3. incomplete western blot seroconversion + 26 million copies of virus RNA/mL Clinical highlights • Patient joined the cohort of HIV primary infection at March 1999. Man, 54 years old, infected in Thailand after unprotected sexual intercourse “MSM”.

  4. Evolution of CD4+ counts and HIV-1 viral loads Spontaneous treatment interruption

  5. Clinical evolution In the absence of HAART since 2000: Why? • Asymptomatic • Viremia control • CD4 counts above 1500 cells/mL Clinical evolution of a nonprogressor

  6. Locus A Locus B Locus B Host genetic factors associated to clinical outcome CCR5genotype PCR-based assay  Patient HLA Class I typing Two-digit PCR CCR5/CCR5 CCR5/ 32 del. 189-bp 157-bp A3/AX/B7/B40 Wild-type homozygous HLA alleles not associated to disease protection

  7. nested PCR AE recombinants:CRF01 CRF15 CRF11 partial sequencing A1 CRF02 gag 460-bp pol 1496-bp env 500-bp vif 600-bp nef 700-bp CRF03 A2 CRF09 CRF14 G CRF06 CRF13 CRF04 F CRF12 K H J D CRF05 CRF10 B CRF07 CRF08 C Virus subtype assignment: 1 gag alignment of 451-bp comparing patient’s viral sequences to reference sequences. Bootstrap resampling was perform 1000 times . Neighbor-joining tree

  8. Baseline gag AE/B recombinant forms Los Alamos, HIV Sequence Database: February 22th, 2006 CRF15_01B Tovanabutra, 2005 May 25th 2006 CRF33_01B K.P. Ng & K.K. Tee CRF34_01B F.M. McCutchan NCBI.NIH Genotyping Virus subtype assignment: 2 AE/B recombinant according to partial sequences of gag, pol, env, nef and vif

  9. Specific Cellular immune response 28 pools with 183 peptides known as CD8 and CD4 T-cell epitopes mainly described among HIV-1 subtype B infected individuals. HIV Molecular Immunology Database, Los Alamos

  10. Cellular immune responsescreening To measure overall pool responses IFN- ELISpot To confirm single peptide CD8+ T-cell responses IFN- and IL-2 ICS

  11. IFN- ELISpot Matrix Timepoint: 2001

  12. Week 3 (1999) 2005 0 0 0.02 0.02 0 1.51 1.22 0.1 0 0.08 0.01 0.07 0.04 0 0.03 0.19 ICS screening of consensus CD8+ T-Cell Epitopes Week 135 (2001) 0 Neg 0.02 2.15 Gag (HLA-B7) GPGHKARVL 2.65 IL-2 0.09 ENV (HLA-B7) IPRRIRQGL 0.07 0.02 Vif (HLA-A3) HMYISKKAK 0.08 vv IFN-

  13. Cellular Immune responses to clade B peptides • No CD4+ T-cell responses to the matrix peptides were detected. Although weak responses to Gag were present at baseline when using “overlapping peptides”. • Among CD8+ T-cell responses a high magnitude response to gag GPGHKARVL epitope was present from early phase of infection as a monofunctional IFN- response shifting to a high magnitud polyfunctional IFN- +IL2 response at chronic phase of infection.

  14. Which isp24 (223-231) autologous virus sequence? Cellular Immune response to autologous virus

  15. Conserved motif: Conserved motif A, C, D, CRF01_AE G S GPSHKARV GAG p24 (223-231) autologous peptide CTL epitope HLA-B7 restricted in subtype B and C infections. Goulder, 2000; Kiepiela, 2004

  16. ICS screening of consensus vs autologous CD8+ T-cell Gag epitope Week 3 (1999) Week 135 (2001) 2005 0 2.15 1.51 Gag consensus peptide (B7) GPGHKARVL IL-2 0.10 2.65 1.22 0.02 4.08 2.52 Gag autologous peptide (B7) GPSHKARVL 0.20 2.30 0.81 IFN-

  17. Conclusions • Additionally, GPSHKARVL motif conservation among different HIV-1 group M subtypes and CRFs, underlines its relevance for vaccine trial monitoring. We show that GPSHKARVL Gag-p24 (223-231)is a CD8+ T-cell epitope in a HLA-B7 patient harboring a non- progressive HIV-1 AE recombinant infection. • Polyfunctional CD8+ T-cell responses might contribute to viral control and clinical outcome in this patient.

  18. Ongoing analysis VIROLOGIC SCREENING Near full-length genome characterization. Viral fitness. SPECIFIC IMMUNE RESPONSE • CD8+ T-cell immune responses to Env and Vif epitopes that emerged during chronic phase of infection.

  19. Giuseppe Pantaleo1 Alexandre Harari1 Cristina Cellerai1 Pierre-Alexandre Bart1 Jean-Philippe Chave2 Gonzalo Tapia1 1Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, 2 Division of Infectious Diseases, Lausanne University Hospital, Vaud, Switzerland. NIH AIDS Research and Reference Reagent Program

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