Anti‐HIV‐1 immunotoxin 3B3(Fv)‐PE38: enhanced potency against clinical isolates in human PBMCs and macrophages, and negligible hepatotoxicity in macaques

Highly active antiretroviral therapy (HAART) against human immunodeficiency virus type 1 (HIV-1) infection dramatically suppresses viral load, leading to marked reductions in HIV-1 associ- ated morbidity and mortality. However, infected cell reservoirs and low-level replication persist in the face of suppressive HAART, leading invariably to viral rebound upon cessation of treatment. Toxins engi- neered to target the Env glycoprotein on the surface of productively infected cells represent a comple- mentary strategy to deplete these reservoirs. We described previously highly selective killing of Env- expressing cell lines by CD4(178)-PE40 and 3B3(Fv)-PE38, recombinant derivatives of Pseudo- monas aeruginosa exotoxin A containing distinct tar- geting moieties against gp120. In the present report, we compare the in vitro potency and breadth of these chimeric toxins against multiple clinical HIV-1 iso- lates, replicating in biologically relevant primary hu- man target cell types. In PBMCs, 3B3(Fv)-PE38 blocked spreading infection by all isolates examined, with greater potency than CD4(178)-PE40. 3B3(Fv)-PE38 also potently inhibited spreading HIV-1 infection in primary macrophages. Control experiments demonstrated that in both target cell types, most of the 3B3(Fv)-PE38 activity was due to selective killing of infected cells, and not merely to neutralization by the antibody moiety of the chimeric toxin. High-dose treatment of rhesus macaques with 3B3(Fv)-PE38 did not induce liver toxicity, whereas equivalent dosage of CD4(178)-PE40 induced mild hepatotoxicity. These findings highlight the potential use of 3B3(Fv)-PE38 for depleting HIV-infected cell reservoirs persisting in the face of HAART. J. Leu- koc. Biol. 80: 1175-1182; 2006.