title: Combination of Antiretroviral Drugs and Radioimmunotherapy Specifically Kills Infected Cells from HIV-Infected Individuals.
abstract: Eliminating virally infected cells is an essential component of any HIV eradication strategy. Radioimmunotherapy (RIT), a clinically established method for killing cells using radiolabeled antibodies, was recently applied to target HIV-1 gp41 antigen expressed on the surface of infected cells. Since gp41 expression by infected cells is likely downregulated in patients on antiretroviral therapy (ART), we evaluated the ability of RIT to kill ART-treated infected cells using bothin vitromodels and lymphocytes isolated from HIV-infected subjects. Human peripheral blood mononuclear cells (PBMCs) were infected with HIV and cultured in the presence of two clinically relevant ART combinations. Scatchard analysis of the 2556 human monoclonal antibody to HIV gp41 binding to the infected and ART-treated cells demonstrated sufficient residual expression of gp41 on the cell surface to warrant subsequent RIT. This is the first time the quantification of gp41 post-ART is being reported. Cells were then treated with Bismuth-213-labeled 2556 antibody. Cell survival was quantified by Trypan blue and residual viremia by p24 ELISA. Cell surface gp41 expression was assessed by Scatchard analysis. The experiments were repeated using PBMCs isolated from blood specimens obtained from 15 HIV-infected individuals: 10 on ART and 5 ART-naïve. We found that213Bi-2556 killed ART-treated infected PBMCs and reduced viral production to undetectable levels. ART and RIT co-treatment was more effective at reducing viral loadin vitrothan either therapy alone, indicating that gp41 expression under ART was sufficient to allow213Bi-2556 to deliver cytocidal doses of radiation to infected cells. This study provides proof of concept that213Bi-2556 may represent an innovative and effective targeting method for killing HIV-infected cells treated with ART and supports continued development of213Bi-2556 for co-administration with ART toward an HIV eradication strategy.
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Tsukrov
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: McFarren
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements , Karlsruhe , Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements , Karlsruhe , Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Dolce
authors.affiliation: New York University School of Medicine , New York, NY , USA.
authors.forename: Miroslaw K
authors.initials: MK
authors.lastname: Gorny
authors.affiliation: New York University School of Medicine, New York, NY, USA; Veterans Affairs New York Harbor Healthcare System, New York, NY, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Ellie
authors.initials: E
authors.lastname: Schoenbaum
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Zingman
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.affiliation: Albert Einstein College of Medicine , Bronx, NY , USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Dadachova
keywords: HIV; antiretroviral therapy; bismuth-213; gp41; patients; radioimmunotherapy