Postdoctoral Scholar Duke University School of Medicine Hillsborough, North Carolina, United States
Disclosure(s):
Haleigh Conley, PhD: No financial relationships to disclose
Introduction/Rationale: Neutrophil antimicrobial responses are triggered by direct pathogen recognition or binding of antibody-antigen immune complexes (ICs) to cell-surface receptors. Although known to be critical for control of diverse bacterial and viral infections, neutrophil responses to HIV-1 and HIV-antibody ICs (HIV-ICs), remain poorly defined. We hypothesized that HIV-ICs enhance neutrophil antiviral activity and that antibody specificity and subclass influence virus elimination.
Methods: HIV-ICs were formed by incubating monoclonal antibodies (mAbs) with fluorescent HIV-1 virions. Peripheral blood neutrophils were exposed to HIV and HIV-ICs. Phagocytosis was assessed by flow cytometry and microscopy. To test viral inactivation, HIV-IC-loaded neutrophils were co-cultured with permissive cells containing an HIV-driven luciferase reporter gene. Neutrophil activation, degranulation, and reactive oxygen species (ROS) production were measured following phagocytosis. Matrix metalloproteinase-9 levels in supernatants were measured to evaluate degranulation.
Results: HIV-ICs formed with IgG3 mAbs induce more than double the binding and phagocytosis of HIV than IgG1 mAbs, and 30-fold more than free HIV virions. Phagocytosis effectively removed infectious HIV, though non-internalized HIV could be transferred from neutrophils to permissive cells. Surprisingly, we found that neutrophils did not produce robust ROS or significant release of cytotoxic granules in response to HIV-ICs. Consistent with these latter findings, we did not observe significant changes in the activation state of neutrophils following stimulation with HIV-ICs.
Conclusion: Our findings reveal that while HIV-ICs mediate neutrophil binding and phagocytosis of HIV-1, these interactions do not trigger additional antimicrobial responses. Moreover, neutrophils can transfer extracellularly bound, but not internalized, HIV-1 to permissive cells. These findings reveal that neutrophils can limit HIV transmission only through successful internalization of HIV-ICs.
