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Published online before print August 21, 2006

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(Journal of Leukocyte Biology. 2006;80:1175-1182.)
© 2006 by Society for Leukocyte Biology

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

Paul E. Kennedy^*, Tapan K. Bera, Qing-Cheng Wang, Maria Gallo, Wendeline Wagner, Mark G. Lewis, Edward A. Berger^*,1 and Ira Pastan

^* Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases and
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and
Southern Research Institute, Frederick, Maryland, USA

¹ Correspondence: Laboratory of Viral Diseases, NIAID National Institutes of Health Building 4, Room 237 Bethesda, MD 20892, USA. E-mail: edward_berger{at}nih.gov

ABSTRACT

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 associated 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 engineered to target the Env glycoprotein on the surface of productively infected cells represent a complementary 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 Pseudomonas aeruginosa exotoxin A containing distinct targeting moieties against gp120. In the present report, we compare the in vitro potency and breadth of these chimeric toxins against multiple clinical HIV-1 isolates, replicating in biologically relevant primary human 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.

Key Words: HAART • reservoirs persistence • targeted killing

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