VH1-69 Utilizing Antibodies Are Capable of Mediating Non-neutralizing Fc-Mediated Effector Functions Against the Transmitted/Founder gp120

Front Immunol. 2019 Jan 15:9:3163. doi: 10.3389/fimmu.2018.03163. eCollection 2018.


Multiple antibody effector functions arise in HIV-1 infection that could be harnessed to protect against infection or clear the persistent reservoir. Here, we have investigated the genetic and functional memory B cell and antibody landscape present during early infection in six individuals infected with either subtype A, C, or an A/C recombinant HIV-1. These individuals demonstrated varying levels of plasma autologous neutralization (nAb) against the transmitted/founder envelope (T/F Env) pseudovirus and non-neutralizing Fc-mediated effector function (nnFc) antibody-dependent cell-mediated cytotoxicity (ADCC) against the T/F Env gp120 protein at ~7 months after infection. Genetic analysis of the immunoglobulin heavy (VH) and light (VL) chain variable domain gene segments from 352 autologous T/F Env gp120-specific single B cells recovered at this same 7-month time-point revealed an over-representation of the VH1-69 germline in five of six individuals. A defining feature of the VH1-69 utilizing gp120-specific antibodies was their significantly more hydrophobic complementarity-determining region-2 (CDRH2) regions compared to other VH CDRH2 sequences from each individual. While none of the VH1-69 antibodies possessed strong neutralizing activity against virions pseudotyped with the autologous T/F Env, almost a third were capable of mediating high ADCC activity, as assayed by intracellular granzyme B activity in CEM.NKr.CCR5 target cells coated with autologous T/F Env gp120. High ADCC mediating VH1-69 antibodies exhibited shorter complementarity-determining region-3 (CDRH3) lengths and a more neutral isoelectric point than antibodies lacking this function. In the individual that developed the highest autologous ADCC responses, the high granzyme B producing antibodies bound to surface expressed envelope in the absence of CD4 and were not enhanced by the addition of soluble CD4. Overall, VH1-69 utilizing antibodies are commonly induced against gp120 in diverse HIV-1 infections and a subset of these antibodies can mediate ADCC functions, serving as a bridge between the innate and adaptive immune response to HIV-1.

Keywords: HIV-1; VH1-69; gp120; neutralization; non-neutralizing Fc-mediated effector function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD4 Antigens / blood
  • Cell Line
  • Complementarity Determining Regions / immunology
  • Complementarity Determining Regions / metabolism
  • Epitopes / immunology
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / antagonists & inhibitors
  • HIV Envelope Protein gp120 / immunology*
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Fc Fragments / immunology*
  • Immunoglobulin Heavy Chains / chemistry
  • Immunoglobulin Heavy Chains / immunology*
  • Immunoglobulin Variable Region / chemistry
  • Immunoglobulin Variable Region / immunology*
  • Immunologic Memory


  • Antibodies, Monoclonal
  • CD4 Antigens
  • Complementarity Determining Regions
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Immunoglobulin Fc Fragments
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region