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

Abstract

In the RV144 vaccine trial, two antibody responses were found to correlate with HIV-1 acquisition. Because human leukocyte antigen (HLA) class II-restricted CD4(+) T cells are involved in antibody production, we tested whether HLA class II genotypes affected HIV-1-specific antibody levels and HIV-1 acquisition in 760 individuals. Indeed, antibody responses correlated with acquisition only in the presence of single host HLA alleles. Envelope (Env)-specific immunoglobulin A (IgA) antibodies were associated with increased risk of acquisition specifically in individuals with DQB1*06. IgG antibody responses to Env amino acid positions 120 to 204 were higher and were associated with decreased risk of acquisition and increased vaccine efficacy only in the presence of DPB1*13. Screening IgG responses to overlapping peptides spanning Env 120-204 and viral sequence analysis of infected individuals defined differences in vaccine response that were associated with the presence of DPB1*13 and could be responsible for the protection observed. Overall, the underlying genetic findings indicate that HLA class II modulated the quantity, quality, and efficacy of antibody responses in the RV144 trial.

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.