Chimeric toxins targeted to the human immunodeficiency virus type 1 envelope glycoprotein augment the in vivo activity of combination antiretroviral therapy in thy/liv-SCID-Hu mice.
Highly active antiretroviral therapy (HAART), which combines multiple inhibitors of essential human immunodeficiency virus type 1 (HIV-1) enzymes, induces dramatic and sustained viral load reductions in many people infected with HIV-1. However, reservoirs of infected cells capable of producing replication-competent virus persist even after years of HAART, preventing elimination of infection. CD4-PE40 and 3B3(Fv)-PE38, chimeric toxins designed to target the HIV envelope (Env), represent a complementary class of agents that selectively kill productively infected cells. To investigate whether these Env-targeted toxins might serve as adjuncts to HAART for the elimination of infected cells, we tested their ability to augment HAART efficacy in vivo by using a thy/liv SCID-hu mouse model. CD4-PE40 and 3B3(Fv)-PE38 markedly enhanced the capacity of HAART to suppress acute HIV-1 infection and improved HAART-mediated viral load reduction in mice with established HIV-1 infection. These results represent the first demonstration of in vivo anti-HIV-1 efficacy for Env-targeted toxins and support their potential therapeutic utility in combination with HAART.
Goldstein
H
H
Department of Pediatrics and of Microbiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. hgoldste@aecom.yu.edu
Pettoello-Mantovani
M
M
Bera
T K
TK
Pastan
I H
IH
Berger
E A
EA
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D015497:HIV-1; D006801:Humans; D008099:Liver / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013950:Thymus Gland / Q000276:immunology; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors*
D019380:Anti-HIV Agents; D011993:Recombinant Fusion Proteins; D014759:Viral Envelope Proteins