In vitro Evidence That Combination Therapy With CD16-Bearing NK-92 Cells and FDA-Approved Alefacept Can Selectively Target the Latent HIV Reservoir in CD4+ CD2hi Memory T Cells

Front Immunol. 2018 Nov 5;9:2552. doi: 10.3389/fimmu.2018.02552. eCollection 2018.

Abstract

Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be distinguishable from uninfected cells. CD2 was recently identified as a potential marker enriched in the HIV-1 reservoir on CD4+ T cells, the largest, longest-lived and best-characterized constituent of the HIV reservoir. We previously proposed to repurpose FDA-approved alefacept, a humanized α-CD2 fusion protein, to reduce the HIV reservoir in CD2hi CD4+ memory T cells. Here, we show the first evidence that alefacept can specifically target and reduce CD2hi HIV infected cells in vitro. We explore a variety of natural killer (NK) cells as mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) including primary NK cells, expanded NK cells as well as the CD16 transduced NK-92 cell line which is currently under study in clinical trials as a treatment for cancer. We demonstrate that CD16.NK-92 has a natural preference to kill CD2hi CD45RA- memory T cells, specifically CD45RA- CD27+ central memory/transitional memory (TCM/TM) subset in both healthy and HIV+ patient samples as well as to reduce HIV DNA from HIV+ samples from donors well controlled on antiretroviral therapy. Lastly, alefacept can combine with CD16.NK-92 to decrease HIV DNA in some patient samples and thus may yield value as part of a strategy toward sustained HIV remission.

Keywords: ADCC; CD16; CD2; FDA; HIV; NK; NK92; alefacept.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Alefacept / therapeutic use*
  • Anti-HIV Agents / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Biomarkers / metabolism
  • CD2 Antigens / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • DNA, Viral / genetics
  • Drug Therapy, Combination
  • GPI-Linked Proteins / metabolism
  • HIV Infections / drug therapy*
  • HIV-1 / immunology
  • Humans
  • Immunologic Memory / immunology
  • Jurkat Cells
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / transplantation*
  • Leukocyte Common Antigens / metabolism
  • Receptors, IgG / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism
  • Virus Latency / drug effects*

Substances

  • Anti-HIV Agents
  • Biomarkers
  • CD2 Antigens
  • DNA, Viral
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Receptors, IgG
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Leukocyte Common Antigens
  • Alefacept