HIV-1 Env- and Vpu-Specific Antibody-Dependent Cellular Cytotoxicity Responses Associated with Elite Control of HIV

Abstract

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.

Dimeric FcγR ectodomains detect pathogenic anti‐platelet factor 4–heparin antibodies in heparin‐induced thromobocytopenia

“…Dimeric rsFcγRIIa binding requires closely spaced pairs of antibodies, as occurs in ICs , and has been used to detect FcγR functional antibodies against influenza virus and HIV envelope proteins . HIT pathogenesis requires Fc‐mediated clustering of platelet FcγRIIa, but two SRA‐positive samples were not detected with the dimeric rsFcγRIIa‐binding assay.…”

Vaccinating for natural killer cell effector functions

“…CD57 + NKG2C + memory‐like NK cells are expanded in HIV‐1/HCMV co‐infected individuals, and these cells make a potential contribution to control of viremia during primary HIV infection . Together with evidence that individuals with a degree of inherent resistance to HIV – so‐called elite controllers or slow progressors – mount stronger antibody‐mediated NK cell activation and ADCC responses than more susceptible individuals, these studies suggest that NK cells may contribute to HIV protection and control …”

“…74,75 Together with evidence that individuals with a degree of inherent resistance to HIVso-called elite controllers or slow progressorsmount stronger antibody-mediated NK cell activation and ADCC responses than more susceptible individuals, these studies suggest that NK cells may contribute to HIV protection and control. 76 NK cells have been implicated as antigenspecific effector cells after vaccination or infection of nonhuman primates with simian immunodeficiency virus (SIV); target cells pulsed with SIV vaccine antigen but not heterologous antigens can be lysed in vitro by splenic and hepatic NK cells from infected but not from uninfected animals. 17 These antigen-specific responses could be detected for at least 5 years after SIV DNA/adenovirus prime-boost vaccination, suggesting that this memory-like response is longlived.…”

A role for antibodies in natural HIV control

“…Several studies did not detect an improved capacity of EC sera to mediate ADCC [56, 74,75]. In contrast, Abs mediating ADCC were found to be increased in other EC cohorts [5,76], with one study reporting a predominant ADCC response in HLA-B*57negative EC, as compared to HLA-B*57-positive EC [77].…”