title: Anti-HIV-1 immunotoxin 3B3(Fv)-PE38: enhanced potency against clinical isolates in human PBMCs and macrophages, and negligible hepatotoxicity in macaques.
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.
authors.affiliation: Laboratory of Viral Diseases, NIAID, National Institutes of Health Building 4, Room 237 Bethesda, MD 20892, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Kennedy
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Bera
authors.forename: Qing-Cheng
authors.initials: QC
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Gallo
authors.forename: Wendeline
authors.initials: W
authors.lastname: Wagner
authors.forename: Mark G
authors.initials: MG
authors.lastname: Lewis
authors.forename: Edward A
authors.initials: EA
authors.lastname: Berger
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006678:HIV / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000821:virology; D008107:Liver Diseases / Q000473:pathology; D008251:Macaca; D008264:Macrophages / Q000187:drug effects* / Q000821:virology; D023421:Models, Animal; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; C057689:CD4-Pseudomonas toxin; D005098:Exotoxins; D000922:Immunotoxins; D011994:Recombinant Proteins