Research ArticleHIV

HLA class II genes modulate vaccine-induced antibody responses to affect HIV-1 acquisition

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Science Translational Medicine  15 Jul 2015:
Vol. 7, Issue 296, pp. 296ra112
DOI: 10.1126/scitranslmed.aab4005
  • Fig. 1. High Env-specific IgA (IgA) levels are associated with increased risk of HIV-1 acquisition only in the presence of HLA-DQB1*06.

    (A) Box plots of vaccinated individuals stratified according to HIV-1 infection status and the absence or presence of DQB1*06. Individual data points are indicated by colored circles within the box plots showing the 25th (bottom edge of the box), 50th (horizontal line in the box), and 75th percentiles (top edge of the box). Analysis of variance tested IgA distributions across subsets with differences further interrogated using Bonferroni-adjusted t tests. MFI, mean fluorescence intensity. (B) Estimated cumulative HIV-1 incidence curves for individuals stratified by IgA and DQB1*06 for the entire vaccinated RV144 cohort. Vaccinated individuals in the case-control study are stratified into subgroups according to their IgA responses (low/medium and high, corresponding to the lower two-thirds and upper one-third of responses) at week 26 and the absence or presence of DQB1*06. Individual curves represent the estimated cumulative incidence of HIV-1 infection over time since the measurement of IgA at week 26. Curves were estimated using the Kaplan-Meier method with inverse probability weighting accounting for the sampling design.

  • Fig. 2. Env (120–204)–specific IgG is associated with the presence of HLA-DPB1*13 and is protective.

    (A) Distribution of IgG stratified by absence or presence of DPB1*13. Red lines represent the mean and SD for the change in the measurement of IgG from absence to presence of DPB1*13. Means were compared using t tests. Individual data points are indicated by black circles. (B) Box plots of vaccinated individuals stratified according to HIV-1 infection status and the absence or presence of DPB1*13. Individual data points are indicated by colored circles within the box plots showing the 25th (bottom edge of the box), 50th (horizontal line in the box), and 75th percentiles (top edge of the box). Analysis of variance tested IgG distributions across subsets with differences further interrogated using Bonferroni-adjusted t tests. (C) Estimated cumulative HIV-1 incidence curves for individuals stratified by IgG and DPB1*13 for the entire vaccinated RV144 cohort. Vaccinated individuals in the case-control study are stratified into subgroups according to their IgG responses (low and high/medium corresponding to the lower one-third and upper two-thirds of responses) at week 26 and the absence or presence of DPB1*13. Individual curves represent the estimated cumulative incidence of HIV-1 infection over time. Curves were estimated using the Kaplan-Meier method with inverse probability weighting accounting for the sampling design. (D) Estimated vaccine efficacy (VE) for IgG and DPB1*13. Individuals were stratified into subgroups according to IgG response (low and high/medium, corresponding to the lower one-third and upper two-thirds of responses) and the absence or presence of DPB1*13 and were compared to the entire placebo-infected group. Points show the estimated VE values, and lines represent 95% confidence intervals (CI) that were estimated using logistic regression models that accounted for the sampling design.

  • Fig. 3. Frequency and magnitude of IgG responses to Env epitope (119–133) are associated with HIV-1 acquisition among DPB1*13 vaccinated individuals.

    (A) Frequency of DPB1*13 restricted peptide responses comparing vaccinated infected (VI) and vaccinated uninfected (VU) individuals that have at least one DPB1*13 allele. Fisher’s exact test compared the frequency of antibody response between VU DPB1*13 and VI DPB1*13 individuals. (B) Red lines represent the mean and SD for the change in the magnitude in responses from absence to presence of DPB1*13. Means were compared using t tests.

  • Table 1. Frequencies of amino acids at site 173 of Env-gp70 differ in breakthrough infections in the presence of the DPB1*13 allele.
    Vaccine (n = 44)Fisher’s PPlacebo (n = 66)Fisher’s P
    DPB1*13+DPB1*13DPB1*13+DPB1*13
    H1738150.0049190.57
    H173X*021929
    DPB1*13+ (n = 26)DPB1*13 (n = 84)
    H173H173XH173H173X
    Vaccine800.0215191.00
    Placebo992129

    *X designates amino acid residues other than histidine (H) at position 173.

    • Table 2. Interactions of HLA class II alleles and vaccine-induced responses have an independent effect on HIV-1 acquisition.

      ORs for HIV-1 acquisition in a multivariable analysis of all primary immune response variables from the immune correlate study (3) and the two significant HLA interactions observed in this study.

      VariableMultivariable model*
      OR (95% CI)P value
      Avidity of IgG antibodies for Env0.94 (0.56–1.57)0.80
      ADCC0.97 (0.62–1.51)0.89
      Neutralizing antibodies1.08 (0.63–1.85)0.78
      Env-specific CD4+ T cells1.07 (0.77–1.50)0.68
      Env-specific IgA-DQB1*06 interaction†8.24 (2.07–32.75)0.003
      Env (120–204)–specific IgG-DPB1*13
      interaction†
      0.27 (0.09–0.80)0.02

      *For each primary immune variable (3), the OR is reported per 1-SD increase; sex, baseline behavioral risk score, and one significant principal component axis were included as covariates in the model. Env-specific IgA, DQB1*06, Env (120–204)–specific IgG, and DPB1*13 were also included as main effects. †Reported ORs and 95% CIs reflect the results from logistic regression analysis including a two-way interaction term for Env-specific IgA or Env (120–204)–specific IgG and the absence or presence of the given allele.

      Supplementary Materials

      • www.sciencetranslationalmedicine.org/cgi/content/full/7/296/296ra112/DC1

        Fig. S1. Multiple alignment of different Env (120–204) and partial V2 sequences (160–183).

        Fig. S2. Cocrystal structure of HIV-1 gp120 (red) binding to CD4 (green) and the Fab of mAb 17b (blue) (23).

        Table S1. Odds ratios for two-way interaction analysis of HLA class II alleles with Env-specific IgA and Env (120–204)–specific IgG.

        Table S2. Association between Env-specific IgA or Env (120–204)–specific IgG and HLA class II alleles present in more than 5% of the study population.

        Table S3. High IgG binding to multiple Env (120–204) antigens correlates with presence of DPB1*13 and is associated with decreased HIV-1 acquisition across multiple subtypes.

        Table S4. IgG responses to five overlapping peptides spanning Env (120–204) were significantly associated with presence of DPB1*13.

        Table S5. Comparison of frequency of amino acid (AA) sites in Env-gp70 in RV144 breakthrough infections stratified by DPB1*13.

        Table S6. Odds ratios for IgA binding to different recombinant Env proteins on HIV-1 acquisition after stratification by absence or presence of HLA-DQB1*06.

        Table S7. Odds ratios for HIV-1 acquisition in univariate analyses of all HLA class II alleles present in the placebo controls.

        Table S8. Odds ratios for HIV-1 acquisition in univariate analyses of all HLA class II alleles present in the vaccinated volunteers.

      • Supplementary Material for:

        HLA class II genes modulate vaccine-induced antibody responses to affect HIV-1 acquisition

        Heather A. Prentice, Georgia D. Tomaras, Daniel E. Geraghty, Richard Apps, Youyi Fong, Philip K. Ehrenberg, Morgane Rolland, Gustavo H. Kijak, Shelly J. Krebs, Wyatt Nelson, Allan DeCamp, Xiaoying Shen, Nicole L. Yates, Susan Zolla-Pazner, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, Guido Ferrari, M. Juliana McElrath, David C. Montefiori, Robert T. Bailer, Richard A. Koup, Robert J. O'Connell, Merlin L. Robb, Nelson L. Michael, Peter B. Gilbert, Jerome H. Kim, Rasmi Thomas*

        *Corresponding author. E-mail: rthomas{at}hivresearch.org

        Published 15 July 2015, Sci. Transl. Med. 7, 296ra112 (2015)
        DOI: 10.1126/scitranslmed.aab4005

        This PDF file includes:

        • Fig. S1. Multiple alignment of different Env (120–204) and partial V2 sequences (160–183).
        • Fig. S2. Cocrystal structure of HIV-1 gp120 (red) binding to CD4 (green) and the Fab of mAb 17b (blue) (23).
        • Table S1. Odds ratios for two-way interaction analysis of HLA class II alleles with Env-specific IgA and Env (120–204)–specific IgG.
        • Table S2. Association between Env-specific IgA or Env (120–204)–specific IgG and HLA class II alleles present in more than 5% of the study population.
        • Table S3. High IgG binding to multiple Env (120–204) antigens correlates with presence of DPB1*13 and is associated with decreased HIV-1 acquisition across
          multiple subtypes.
        • Table S4. IgG responses to five overlapping peptides spanning Env (120–204) were significantly associated with presence of DPB1*13.
        • Table S5. Comparison of frequency of amino acid (AA) sites in Env-gp70 in RV144 breakthrough infections stratified by DPB1*13.
        • Table S6. Odds ratios for IgA binding to different recombinant Env proteins on HIV-1 acquisition after stratification by absence or presence of HLA-DQB1*06.
        • Table S7. Odds ratios for HIV-1 acquisition in univariate analyses of all HLA class II alleles present in the placebo controls.
        • Table S8. Odds ratios for HIV-1 acquisition in univariate analyses of all HLA class II alleles present in the vaccinated volunteers.

        [Download PDF]

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