A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier

Objective: Many HIV patients on combined antiretroviral therapy exhibit HIV-associated neurocognitive disorders because the brain becomes a viral reservoir. There is a need for therapeutics that can enter the central nervous system (CNS) and eradicate the virus. Design: Radiolabeled human mAb 2556 to HIV gp41 selectively kills HIV-infected cells in vivo and in vitro. Here we tested the ability of 213Bi-2556 to cross a tissue culture model of the human blood brain barrier and kill HIV-infected peripheral blood mononuclear cells (PBMCs) and monocytes on the CNS side of the barrier. Methods: 2556 mAb isoelectric point was determined with isoelectric focusing. The ability of radiolabeled 2556 to penetrate through the barrier was studied by adding it to the upper chamber of the barriers and its penetration into the CNS side was followed for 5 h. To assess the ability of 213Bi-2556 to kill the HIV-infected cells on the CNS side of barrier, the HIV-infected and uninfected PBMCs and monocytes were allowed to transmigrate across the barriers overnight followed by application of 213Bi-2556 or control mAb 213Bi-1418 to the top of the barrier. Killing of cells was measured by TUNEL and Trypan blue assays. The barriers were examined by confocal microscopy for overt damage. Results: The isoelectric point of 213Bi-2556 was 9.6 enabling its penetration through the barrier by transcytosis. 213Bi-2556 killed significantly more transmigrated HIVinfected cells in comparison to 213Bi-1418 and uninfected cells. No overt damage to barriers was observed. Conclusion: We demonstrated that 213Bi-2556 mAb crossed an in-vitro human blood brain barrier and specifically killed transmigrated HIV-infected PBMCs and monocytes without overt damage to the barrier.

MCFARREN A;  LOPEZ L;  WILLIAMS D;  VEENSTRA Mike;  BRYAN R. A.;  GOLDSMITH Aliza;  MORGENSTERN Alfred;  BRUCHERTSEIFER Frank;  ZOLLA-PAZNER S.;  GORNY M.K.;  EUGENIN E;  BERMAN J;  DADACHOVA E.; 

2016-02-25

LIPPINCOTT WILLIAMS & WILKINS

JRC82865

0269-9370,   

https://publications.jrc.ec.europa.eu/repository/handle/JRC82865,   

10.1097/QAD.0000000000000968,