Polyanionic (i.e., polysulfonate) dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps (Reverse transcriptase/integrase) in the virus replicative cycle

Polyanionic dendrimers were synthesized and evaluated for their antiviral e ffects. Phenyldicarboxylic acid (BRI6195) and naphthyldisulfonic acid (BRI2 923) dendrimers were found to inhibit the replication of human immunodefici ency virus type 1 (HIV-1; strain IIIB) in MT-4 cells at a EC50 of 0.1 and 0 .3 mu g/ml, respectively. The dendrimers were not toxic to MT-4 cells up to the highest concentrations tested (250 mu g/ml). These compounds were also effective against various other HIV- 1 strains, including clinical isolate s, HIV-2 strains, simian immunodeficiency virus (SIV, strain MAC(251)), and HIV-1 strains that were resistant to reverse transcriptase inhibitors. HIV strains containing mutations in the envelope glycoprotein gp120 (engenderi ng resistance to known adsorption inhibitors) displayed reduced sensitivity to the dendrimers. The compounds inhibited the binding of wild-type virus and recombinant virus (containing wild-type gp120) to MT-4 cells at concent rations comparable to those that inhibited the replication of HIV- 1(IIIB) in these cells. Cellular uptake studies indicated that BRI2923, but not BRI 6195, permeates into MT-4 and CEM cells. Accordingly, the naphtyldisulfonic acid dendrimer (BRI2923) proved able to inhibit later steps of the replica tion cycle of HIV, i.e., reverse transcriptase and integrase. NL4.3 strains resistant to BRI2923 were selected after passage of the virus in the prese nce of increasing concentrations of BRI2923. The virus mutants showed 15-fo ld reduced sensitivity to BRI2923 and cross-resistance to known adsorption inhibitors. However, these virus mutants were not cross-resistant to revers e transcriptase inhibitors or protease inhibitors. We identified several mu tations in the envelope glycoprotein gp120 gene (i.e., V2, V3, and C3, V4, and C4 regions) of the BRI2923-resistant NL4.3 strains that were not presen t in the wild-type NL4.3 strain, whereas no mutations were found in the rev erse transcriptase or integrase genes.