Activity of Cu2Zn2 superoxide dismutase against the human immunodeficiency virus type 1

The anti-retroviral activity of Cu2Zn2 superoxide dismutase (SOD; EC 1.15.1.1) was tested in Molt-4 cells infected with the human immunodeficiency virus type 1 (HIV-1) and compared to the anti-HIV-1 activity of the reverse transcriptase inhibitors azidothymidine (AZT), dideoxycytidine (ddC), dideoxyuridine (ddU) and phosphono-formic acid, the glucosidase I inhibitors castanospermine and dihydroxymethyl dihydroxy-pyrrolidine (DMDP), the HIV protease inhibitor RO-31-7595 as well as the CD4-masking compound aurintricarboxylic acid. 300 nM of SOD sufficed to reduce the release of the viral antigen gp 120 of HIV-1NDK-infected Molt-4 cells by 50% [EC50]. Cytotoxic effects of SOD were estimated by cell counts and rates of cell growth. SOD, 3 μM, reduced the cell growth of uninfected cells by 50% [TC50]. While copper-free apo-SOD displayed no anti-HIV activity, the [EC50] of heat-inactivated enzyme was 1 μM, suggesting an anti-retroviral effect of low molecular weight active center degradation products of SOD. The [EC50] of SOD reached 10% of AZT's anti-HIV-1NDK activity and exceeded all tested anti-retrovirals 40-3000-fold. The selectivity index (Si= [TC50]/[EC50) for SOD was 10, resembling the reverse transcriptase inhibitors dideoxycytidine and phosphonoformic acid. SOD inhibited also dose-dependently the oxidative stress induced depletion of sulfhydryls, which are crucially involved in the nuclear factor kappa B controlled HIV transcription.