Immune Correlates Identified in the RV144 Vaccine Efficacy Trial Impact HIV-1 Acquisition Only in the Presence of Certain HLA Class II Genes

Background: Two immune correlates were identified as predictors of risk of infection in the RV144 HIV-1 vaccine clinical trial. Binding of plasma IgA antibodies (IgA) to HIV-1 envelope (Env) correlated directly with acquisition whereas binding of IgG antibodies to an antigen containing the variable regions 1 and 2 of Env (IgG) correlated inversely with acquisition. We hypothesized that HLA class II molecules expressed on antigen presenting cells modulate CD4 T cell stimulation of antibody production by B cells involved in vaccine-induced responses.

Methods: HLA class II genes were genotyped in the case-control group of 205 uninfected and 41 infected RV144 vaccinated volunteers. The interaction of HLA-DPB1, DQB1 and DRB1 alleles with IgA and IgG immune responses was tested for an effect on acquisition by logistic regression.

Results: DQB1*06 (p=0.002, q=0.06), DPB1*05 (p=0.03, q=0.19), and DPB1*13 (p=0.04, q=0.20) had a significant interaction with IgA antibody responses on acquisition. Increased IgA levels associated with increased risk for infection only in the presence of DQB1*06. In contrast, IgA levels did not associate with increased risk for infection in the presence of DPB1*05 and *13. Further, high IgG antibody levels directly correlated with the presence of DPB1*13 allele. IgG V1V2 antibodies were associated with reduced acquisition risk only in the presence of DPB1*13 (OR=0.3, p=0.007) with no association observed in the absence of DPB1*13. The observed interactions for DQB1*06 with IgA and DPB1*13 with IgG remained significant in a multivariable model when testing other primary variables including IgG avidity, antibody-dependent cellular cytotoxicity, neutralizing antibodies, and Env-specific CD4+T cells.

Conclusions: These associations suggest that certain HLA class II genes modulated the effect of antibody responses to the RV144 vaccine and impacted HIV-1 acquisition. Understanding this HLA class II mechanism will enable improved HIV vaccine design.