title: Cobalamin inhibition of HIV-1 integrase and integration of HIV-1 DNA into cellular DNA.
abstract: 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 inhibited in vitro by hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl), adenosylcobalamin (Ado-Cbl), and dicyanocobinamide (CN2-Cbi) with IC50 values of approximately 17, 17, 17, and 4 microM, respectively. The agents inhibited HIV-1 infection of cultured monocytes (IC50 values for OH-Cbl, Me-Cbl, Ado-Cbl, and CN2-Cbi of 6, 7, 4, and 1 microM, respectively) and of cultured lymphocytes (IC50 values of 60, 50, 60, and 11 microM, 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.
authors.affiliation: VA Medical Center, Durham, North Carolina 27705, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Weinberg
authors.forename: D C
authors.initials: DC
authors.lastname: Shugars
authors.forename: P A
authors.initials: PA
authors.lastname: Sherman
authors.forename: D L
authors.initials: DL
authors.lastname: Sauls
authors.forename: J A
authors.initials: JA
authors.lastname: Fyfe
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D003038:Cobamides / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D006879:Hydroxocobalamin / Q000494:pharmacology; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D009000:Monocytes / Q000187:drug effects / Q000821:virology; D016133:Polymerase Chain Reaction; D016662:Virus Integration / Q000187:drug effects*; D014805:Vitamin B 12 / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D003038:Cobamides; D017931:DNA Primers; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; C019476:mecobalamin; C000913:cobamamide; D014805:Vitamin B 12; D006879:Hydroxocobalamin