COBALAMIN INHIBITION OF HIV-1 INTEGRASE AND INTEGRATION OF HIV-1 DNA INTO CELLULAR DNA

Our prior studies showed that certain cobalamins inhibit productive HI V-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 infe ction. Purified recombinant HIV-1 integrase activity was inhibited in vitro by hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl), adenosyl cobalamin (Ado-Cbl), and dicyanocobinamide (CN(2)Cbi) with IC50 values of approximately 17, 17, 17, and 4 mu M, respectively. The agents inh ibited HIV-1 infection of cultured monocytes (IC50 values for OH-Cbl, Me-Cbl, Ado-Cbl, and CN2-Cbi of 6, 7, 4, and 1 mu M, respectively) and of cultured lymphocytes (IC50 values of 60, 50, 60, and 11 mu M, resp ectively). Experiments using cultured monocytes or lymphocytes demonst rated 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 treatm ents that target HIV-1 integrase. (C) 1998 Academic Press.