TY - JOUR
T1 - Targeted killing of virally infected cells by radiolabeled antibodies to viral proteins
AU - Dadachova, Ekaterina
AU - Patel, Mahesh C.
AU - Toussi, Sima
AU - Apostolidis, Christos
AU - Morgenstern, Alfred
AU - Brechbiel, Martin W.
AU - Gorny, Miroslaw K.
AU - Zolla-Pazner, Susan
AU - Casadevall, Arturo
AU - Goldstein, Harris
PY - 2006/11
Y1 - 2006/11
N2 - 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. Methods and Findings: Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 (213Bi) and rhenium 188 (188Re) 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 213Bi- or 188Re-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 188Re-labeled antibody to gp41 compared with those treated with the 188Re-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.
AB - 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. Methods and Findings: Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 (213Bi) and rhenium 188 (188Re) 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 213Bi- or 188Re-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 188Re-labeled antibody to gp41 compared with those treated with the 188Re-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.
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U2 - 10.1371/journal.pmed.0030427
DO - 10.1371/journal.pmed.0030427
M3 - Article
C2 - 17090209
AN - SCOPUS:33845316055
SN - 1549-1277
VL - 3
SP - 2094
EP - 2103
JO - PLoS Medicine
JF - PLoS Medicine
IS - 11
ER -