Cobalamin Inhibition of HIV-1 Integrase and Integration of HIV-1 DNA into Cellular DNA

• Published in: Biochemical and biophysical research communications Vol. 246; no. 2; pp. 393 - 397
• Main Authors: Weinberg, J.Brice, Shugars, Diane C., Sherman, Paula A., Sauls, Derrick L., Fyfe, James A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.05.1998
• Subjects: AIDS/HIV; Base Sequence; Cells, Cultured; Cobamides - pharmacology; DNA Primers - genetics; DNA, Viral - drug effects; DNA, Viral - genetics; DNA, Viral - physiology; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Hydroxocobalamin - pharmacology; In Vitro Techniques; Lymphocytes - drug effects; Lymphocytes - virology; Monocytes - drug effects; Monocytes - virology; Polymerase Chain Reaction; Virus Integration - drug effects; Vitamin B 12 - analogs & derivatives; Vitamin B 12 - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1998.8629

Our prior studies showed that certain cobalamins inhibit productive HIV-1 infection of primary cultures of blood lymphocytes and monocytes. We demonstrate here that this antiviral activity may be mediated by an inhibition of HIV-1 integrase, an enzyme required for productive infection. Purified recombinant HIV-1 integrase activity was inhibitedin vitroby hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl), adenosylcobalamin (Ado-Cbl), and dicyanocobinamide (CN2-Cbi) with IC50values of approximately 17, 17, 17, and 4 μM, respectively. The agents inhibited HIV-1 infection of cultured monocytes (IC50values for OH-Cbl, Me-Cbl, Ado-Cbl, and CN2-Cbi of 6, 7, 4, and 1 μM, respectively) and of cultured lymphocytes (IC50values of 60, 50, 60, and 11 μM, respectively). Experiments using cultured monocytes or lymphocytes demonstrated that OH-Cbl inhibited integration of HIV-1 DNA into cellular DNA. Thus, cobalamins and cobinamides represent novel inhibitors of HIV-1 integrase. These or related agents may be useful as anti-viral treatments that target HIV-1 integrase.