PMTI, a broadly active unusual single-stranded polyribonucleotide, inhibits human immunodeficiency virus replication by multiple mechanisms

Poly(1-methyl-6-thioinosinic acid), or PMTI, is a single-stranded polyribon ucleotide and is the first homopolyribonucleotide devoid of Watson-Crick hy drogen bonding sites to show potent human immunodeficiency virus (HIV) inhi bition. PMTI was found to be active when evaluated against a variety of low passage clinical HIV isolates in fresh human peripheral blood cells, inclu ding T cell-tropic and monocyte-macrophage-tropic viruses, syncytium-induci ng and non-syncytium-inducing viruses and viruses representative of the var ious HIV-1 clades (A through F). The compound was active against HIV-2, all nucleoside and non-nucleoside reverse transcriptase (RT) inhibitor drug-re sistant virus isolates tested and interacted with AZT or ddl to synergistic ally inhibit HIV infection. In biochemical inhibition assays, PMTI was dete rmined to be a potent inhibitor of HIV-I and HIV-2 RT,including RTs with mu tations that engender resistance to nucleoside and non-nucleoside RT inhibi tors. PMTI inhibited both the polymerase and RNase H activities of HIV RT. PMTI did not inhibit HIV-1 protease or integrase. Cell-based mechanism of a ction assays indicated that PMTI also interfered with early events in the e ntry of HIV into target cells. Furthermore, PMTI inhibited the fusion of gp 120-expressing and CD4-expressing cells, but at concentrations approximatel y 1 log(10) greater than those that inhibited virus entry. These results su ggest that the homopolyribonucleotide PMTI blocks HIV replication in human cells at its earliest stages by multiple mechanisms, inhibition of virus en try and inhibition of RT.