Cobalamin inhibition of HIV-1 integrase and integration of HIV-1 DNA
into cellular DNA.
Biochemical and biophysical research communications; VOL: 246 (2);
Weinberg JB; Shugars DC; Sherman PA; Sauls DL; Fyfe JA
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.