Studying HIV-infected individuals who control HIV replication (elite controllers [ECs]) enables exploration of effective anti-HIV immunity. HIV Env-specific and nonEnv-specific antibody-dependent cellular cytotoxicity (ADCC) may contribute to protection from progressive HIV infection, but the evidence is limited. We recruited 22 ECs and matched them with 44 viremic subjects. HIV Env-and Vpu-specific ADCC responses in sera were studied using a novel enzyme-linked immunosorbent assay (ELISA)-based dimeric recombinant soluble Fc␥RIIIa (rsFc␥RIIIa)-binding assay, surface plasmon resonance, antibody-dependent natural killer (NK) cell activation assays, and ADCC-mediated killing assays. ECs had higher levels of HIV Env-specific antibodies capable of binding Fc␥RIIIa, activating NK cells, and mediating granzyme B activity (all P Ͻ 0.01) than viremic subjects. ECs also had higher levels of antibodies against a C-terminal 13-mer Vpu peptide capable of mediating Fc␥RIIIa binding and NK cell activation than viremic subjects (both P Ͻ 0.05). Our data associate Env-specific and Vpu epitope-specific ADCC in effective immune responses against HIV among ECs. Our findings have implications for understanding the role of ADCC in HIV control.IMPORTANCE Understanding immune responses associated with elite control of HIV may aid the development of immunotherapeutic and vaccine strategies for controlling HIV infection. Env is a major HIV protein target of functional antibody responses that are heightened in ECs. Interestingly, EC antibodies also target Vpu, an accessory protein crucial to HIV, which degrades CD4 and antagonizes tetherin. Antibodies specific to Vpu are a common feature of the immune response of ECs that may prove to be of functional importance to the design of improved ADCC-based immunotherapy and preventative HIV vaccines.

Ab-dependent cellular cytotoxicity (ADCC) responses are of growing interest in the HIV vaccine field but current cell-based assays are usually difficult to reproduce across laboratories. We developed an ELISA and multiplex assay to model the cross-linking of Fcγ receptors (FcγR) by Abs, which is required to initiate an ADCC response. Our FcγR dimer ELISA readily detected Abs in samples from two separate cohorts of the partially efficacious Thai RV144 HIV vaccine efficacy trial. The FcγR dimer-binding Abs induced by the RV144 regimen correlated well with a functional measure of ADCC as well as IgG subclasses. The high-throughput multiplex assay allowed us to simultaneously measure FcγR dimer-binding Abs to 32 different HIV Ags, providing a measure of the breadth of FcγR-binding Abs induced by the RV144 trial. FcγR-binding Abs specific to V regions 1 and 2 were strongly associated with increased breadth of recognition of different Env proteins, suggesting anti-V regions 1 and 2 Abs may be a marker of ADCC breadth. This FcγR dimer provides an important tool for the further analysis and refinement of ADCC-inducing HIV and other antiviral vaccine regimens.

This study seeks to assess the ability of seasonal trivalent inactivated influenza vaccine (TIV) to induce nonneutralizing antibodies (Abs) with Fc-mediated functions in HIV-uninfected and HIV-infected subjects. Functional influenza-specific Ab responses were studied in 30 HIV-negative and 27 HIV-positive subjects immunized against seasonal influenza. All 57 subjects received the 2015 TIV.