A potent anti-HIV immunotoxin blocks spreading infection by primary HIV type 1 isolates in multiple cell types.
Although several immunotoxins that selectively kill HIV-1-infected cells have been described, their clinical utility is limited by low potency against spreading viral infection. We show here that changing the carboxyterminal sequence of an anti-HIV-1 envelope immunotoxin to the consensus endoplasmic reticulum retention sequence KDEL substantially improves its ability to block infection of peripheral blood mononuclear cells by primary HIV-1 isolates without increasing nonspecific toxicity. Polychromatic flow cytometry of peripheral blood mononuclear cells (PBMC) infected with an HIV-1-GFP reporter virus demonstrated that the improved immunotoxin is active against a variety of primary cell types including memory T cells, NK-T cells, and monocyte/macrophages. The subnanomolar potency of this agent suggests that it could be clinically useful either as an adjuvant to highly active antiretroviral therapy (HAART) in drug-resistant patients or to reduce the reservoir of latently infected cells that is implicated in HIV-1 persistence.
Lueders
Kira K
KK
Laboratory of Biochemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
De Rosa
Stephen C
SC
Valentin
Antonio
A
Pavlakis
George N
GN
Roederer
Mario
M
Hamer
Dean H
DH
D036002:ADP Ribose Transferases / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D001427:Bacterial Toxins / Q000235:genetics / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D006224:Cricetinae; D005098:Exotoxins / Q000235:genetics / Q000494:pharmacology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D015483:HIV Antibodies / Q000235:genetics / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008164:Luminescent Proteins / Q000235:genetics; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000821:virology; D009842:Oligopeptides; D021382:Protein Sorting Signals; D037521:Virulence Factors / Q000235:genetics / Q000494:pharmacology; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D049452:Green Fluorescent Proteins; D015483:HIV Antibodies; D000922:Immunotoxins; D008164:Luminescent Proteins; D009842:Oligopeptides; D021382:Protein Sorting Signals; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C073762:lysyl-aspartyl-glutamyl-leucine