New approaches to the treatment of AIDS with special reference to overcoming interferon resistance.
This is a brief review on studies of attacking HIV through a new angle. In previous studies, we have found that many patients with AIDS are resistant to interferon (IFN) therapy, and some develop resistance during therapy. Four factors were found to be responsible for the resistance of untreated patients: (a). release of free-circulating IFN-alpha/beta type 1 receptors, (b). a newly detected IFN inhibitory protein, (c). high prostaglandin E2, and (d). high levels of cAMP phosphodiesterases, particularly in AIDS-related neoplasms. This may interfere with intrinsic disease resistance and with the efficacy of IFN therapy. In an attempt to overcome this resistance, new compounds were synthesized which increase endogenous production of alpha, beta and gamma IFNs, have anti-template activity against DNA and RNA polymerases, inhibit reverse transcriptases and activates IFN-induced double-stranded RNA (dsRNA)-dependent protein kinase. It is expected that planned nonhuman primate and clinical studies will support preliminary findings. Preliminary in vitro and animal studies suggest that these new compounds may be effective against HIV, including multi-drug resistant strains.
Ambrus
Julian L
JL
Department of Internal Medicine, Buffalo General Hospital/Kaleida Health System, State University of New York at Buffalo, School of Medicine & Biomedical Sciences and Graduate School, Buffalo, NY 14203, USA. jlambrus@netscape.net
Ambrus
Julian L
JL
Bardos
Thomas J
TJ
Dembinski
W
W
Chadha
Kailash C
KC
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000096:biosynthesis / Q000627:therapeutic use*; D011070:Poly I-C / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D012330:RNA, Double-Stranded / Q000627:therapeutic use; D017471:Receptors, Interferon / Q000378:metabolism
D000998:Antiviral Agents; D012330:RNA, Double-Stranded; D017471:Receptors, Interferon; C043612:poly I-5-mercapto-poly C; D007372:Interferons; D011070:Poly I-C