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Host genetics of T cell responses and Ad5 titers in the STEP trial A CHAVI - HVTN collaboration

Host genetics of T cell responses and Ad5 titers in the STEP trial A CHAVI - HVTN collaboration. David Goldstein Center for Human Genome Variation, Duke University. Adenovirus 5 serology titers.

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Host genetics of T cell responses and Ad5 titers in the STEP trial A CHAVI - HVTN collaboration

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  1. Host genetics of T cell responses and Ad5 titers in the STEP trialA CHAVI - HVTN collaboration David Goldstein Center for Human Genome Variation, Duke University

  2. Adenovirus 5 serology titers Could anti-Ad5 neutralizing antibody titers be merely markers of host genetic factors that confer differential susceptibility to HIV-1?

  3. GWAS – Ad5 titers • CHAVI-001 screening / Malawi • 935 HIV negative participants, >23 years old • Ad5 neutralizing antibodies were measured in Norm Letvin’s lab • Ad5 seroprevalence was very high: 92.6% of the study participants were Ad5 seropositive • STEP trial samples • Pre-vaccination Ad5 titers were analyzed in 3 ethnic groups: Whites (N=348), Hispanics (N=123), Blacks (N=93) • Ad5 seroprevalence was 39% in Whites, 89% in Hispanics and 69% in Blacks

  4. GWAS – Ad5 titers No significant association in any of the analyses

  5. HIV-specific T cell responses • The Merck vaccine was highly immunogenic for inducing HIV-specific T cell responses • HIV-specific T cell responses were quantitatively highly variable • A significant fraction of the unexplained variability in response intensity is likely to be attributable to human genetic variation

  6. GWAS – HIV-specific T cell responses • Subjects: all male vaccine recipients who were HIV seronegative at week 8 (i.e. 4 weeks after the 2nd vaccination) • WG genotyping : Illumina’s Human 1M duo BeadChips • HLA Class I: high-resolution typing using sequence-based methods • Phenotype: HIV-specific T cell responses measured by IFN-γ ELISpot assays • Association study: linear regression models including age, Ad5 titer, ELISpot laboratory (HVTN vs. Merck) and EIGENSTRAT values as covariates.

  7. GWAS – HIV-specific T cell responses  global survey of the host mechanisms associated with variability in T cell responses to the vaccine

  8. Study population - N=774

  9. Results • No genome-wide significant association in any of the analyses • In the analysis of association with quantitative responses to Gag, we observe an enrichment of SNPs from the MHC region among the top p-values, mostly from the genomic region encompassing the HLA-B and HLA-C genes

  10. HLA Class I associations • In Caucasians, HLA-B*2705, *5101 and *5701 associate with higher Gag responses, whereas B*0801 and B*4501 associate with lower responses • Together, these 5 HLA alleles account for 13.6% of the variability in Gag responses

  11. HLA Class I associations P=4.6E-05 P=0.02 P=0.05 P=2.7E-04 P=0.01

  12. HLA Class I associations • Nested regression models demonstrate that they explain most of the association signals detected in the SNP scan

  13. Conclusions I • Human genetic variants located in the MHC region show the strongest association with T cell responses to Gag in HIV negative individuals vaccinated in the STEP trial • HLA-B alleles known to associate with differences in HIV-1 control are essential contributors to the association signal

  14. Conclusions II • The host immunogenetic background modulates individual responses to the Merck Ad5 vaccine • HLA Class I typing data should be considered in the design and analysis of future T cell vaccine studies

  15. Duke University Jacques Fellay Kevin Shianna Liz Cirulli Fred Hutchinson Cancer Research Center Nicole Frahm Daniel Geraghty Juliana McElrath SHARP Alicia Sato NidhiKochar Merck Research Laboratories DaniloCasimiro NCI-Frederick Mary Carrington Harvard Medical School Norm Letvin Connie Gee Carol Lord CHAVI Clinical Core Mike Cohen Clinicians and nurses at Malawi sites

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