Targeted killing of virally infected cells by radiolabeled antibodies to viral proteins.
BACKGROUND
The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo.


RESULTS
Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 ((213)Bi) and rhenium 188 ((188)Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a (213)Bi- or (188)Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the (188)Re-labeled antibody to gp41 compared with those treated with the (188)Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice.


CONCLUSIONS
The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV.
Dadachova
Ekaterina
E
Albert Einstein College of Medicine, Bronx, New York, United States of America. edadacho@aecom.yu.edu
Patel
Mahesh C
MC
Toussi
Sima
S
Apostolidis
Christos
C
Morgenstern
Alfred
A
Brechbiel
Martin W
MW
Gorny
Miroslaw K
MK
Zolla-Pazner
Susan
S
Casadevall
Arturo
A
Goldstein
Harris
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000494:pharmacology*; D001729:Bismuth; D016923:Cell Death; D002478:Cells, Cultured; D003603:Cytotoxins / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015658:HIV Infections / Q000503:physiopathology*; D015497:HIV-1; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000821:virology*; D011868:Radioisotopes; D012211:Rhenium; D013154:Spleen / Q000821:virology; D013601:T-Lymphocytes / Q000821:virology*; D013950:Thymus Gland / Q000637:transplantation / Q000821:virology; D014183:Transplantation, Heterologous; D014764:Viral Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D003603:Cytotoxins; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D011868:Radioisotopes; D014764:Viral Proteins; D012211:Rhenium; D001729:Bismuth