Poster Presentation Second Round 16th Lorne Infection and Immunity 2026

Enhancing antibody-dependent killing of HIV+ target cells by NK cells to advance HIV elimination (#148)

Hans Kek 1 2 , Brianna Jesaveluk 1 , Laura Rikard-Bell 1 2 , Olivia Wilhelm 1 , Christine Jordan 1 , Jingling Zhou 3 , Andy Poumbourios 1 4 , Bruce Wines 1 2 , Anthony Jaworowski 1 3 5 , Anna Hearps 1 5 6
  1. Disease Elimination Program and Life Sciences Discipline, Burnet Institute, Melbourne, VIC, Australia
  2. School of Translational Medicine, Monash University, Melbourne, VIC, Australia
  3. School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
  4. Department of Microbiology, Monash University, Clayton, VIC, Australia
  5. Department of Infectious Diseases, Monash University, Clayton, VIC, Australia
  6. Department of Infectious Diseases, University of Melbourne, Melbourne, VIC, Australia

Background: HIV cure requires the reactivation and elimination of latent reservoirs which persist in T cells and macrophages despite antiretroviral therapy (ART). However, cure trials to date have been hampered by an inability of the endogenous immune system to eliminate reactivated HIV+ cells. Immunotherapy strategies to augment NK cell-mediated elimination of HIV+ cells via antibody dependent cellular cytotoxicity (ADCC) may be useful to enhance HIV elimination in vivo.

Methods: NK cells from people with HIV (PWH) on suppressive ART and seronegative controls were immunophenotyped and their cytotoxic responses to HIV-infected T cells and monocyte derived macrophages assessed via CD107a degranulation. The ability of anti-HIV antibodies with reduced Fc fucosylation to elicit ADCC responses against HIV+ targets was also assessed.

Results: NK cells from PWH showed reduced ADCC activity towards both HIV+ T cells and macrophages as compared to HIV- controls (p<0.001 and 0.01, respectively). Immunophenotyping of degranulating NK cells identified an enhanced ADCC ability of NKG2A+ and KIR3DL2+ NK cells to target HIV+ T cells and macrophages, respectively (p<0.05 for both). However, in PWH the proportion of NKG2A+ NK cells was significantly reduced (19% vs 49% in controls, p=0.03). In contrast, memory-like NK cells (e.g. CD57+, FcRγ-) were expanded in PWH but showed impaired ADCC responses against both cell types. Fc-modification of anti-HIV envelope antibodies including NIH45-46 and 35O22 by afucosylation significantly enhanced ADCC responses of NK cells against HIV+ T cell and macrophage targets.

Conclusion: NK cells from PWH have an impaired ability to target HIV+ cells via ADCC, likely related to immune exhaustion and a skewing of NK cell populations towards memory-like cells with reduced anti-HIV ADCC potential.  Enhancing the ADCC-eliciting potential of anti-HIV antibodies through afucosylation modifications offers the potential to overcome these deficits and enhance ADCC-mediated targeting of HIV+ cells in HIV cure approaches.