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PMTI, a broadly active unusual single-stranded polyribonucleotide, inhibits human immunodeficiency virus replication
R W Buckheit1, C Lackman-Smith, M J Snow
1Microbiology Research Department, Southern Research Institute, Frederick, MD 21701, USA. buckheit@sri.org
Abstract:
Poly(1-methyl-6-thioinosinic acid), or PMTI, is a single-stranded polyribonucleotide and is the first homopolyribonucleotide devoid of Watson-Crick hydrogen bonding sites to show potent human immunodeficiency virus (HIV) inhibition. PMTI was found to be active when evaluated against a variety of low passage clinical HIV isolates in fresh human peripheral blood cells, including T cell-tropic and monocyte-macrophage-tropic viruses, syncytium-inducing and non-syncytium-inducing viruses and viruses representative of the various HIV-1 clades (A through F). The compound was active against HIV-2, all nucleoside and non-nucleoside reverse transcriptase (RT) inhibitor drug-resistant virus isolates tested and interacted with AZT or ddl to synergistically inhibit HIV infection. In biochemical inhibition assays, PMTI was determined to be a potent inhibitor of HIV-1 and HIV-2 RT, including RTs with mutations that engender resistance to nucleoside and non-nucleoside RT inhibitors. 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 action assays indicated that PMTI also interfered with early events in the entry of HIV into target cells. Furthermore, PMTI inhibited the fusion of gp120-expressing and CD4-expressing cells, but at concentrations approximately 1 log10 greater than those that inhibited virus entry. These results suggest that the homopolyribonucleotide PMTI blocks HIV replication in human cells at its earliest stages by multiple mechanisms, inhibition of virus entry and inhibition of RT.
Insights
Poly(1-methyl-6-thioinosinic acid) (PMTI) is a novel homopolyribonucleotide that potently inhibits HIV replication. It blocks early viral entry and reverse transcriptase activity, including in drug-resistant strains.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Poly(1-methyl-6-thioinosinic acid) (PMTI) is a unique single-stranded polyribonucleotide.
- It lacks Watson-Crick hydrogen bonding sites, distinguishing it from other nucleic acids.
- PMTI demonstrates potent activity against human immunodeficiency virus (HIV).
Purpose of the Study:
- To evaluate the antiviral activity of PMTI against diverse HIV isolates.
- To investigate the mechanism of action of PMTI in inhibiting HIV replication.
- To assess PMTI's efficacy against drug-resistant HIV strains and its synergistic potential with existing therapies.
Main Methods:
- In vitro antiviral assays using various clinical HIV-1 and HIV-2 isolates.
- Biochemical assays to determine inhibition of HIV-1 and HIV-2 reverse transcriptase (RT) polymerase and RNase H activities.
- Cell-based assays to examine effects on HIV entry, fusion, and replication.
Main Results:
- PMTI demonstrated potent inhibition against a broad range of HIV isolates, including T-cell tropic, monocyte-macrophage tropic, syncytium-inducing, and various HIV-1 clades.
- It effectively inhibited drug-resistant HIV strains, including those resistant to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs).
- PMTI acted synergistically with AZT and ddl, and inhibited both polymerase and RNase H activities of HIV RT, as well as early viral entry and cell fusion.
Conclusions:
- PMTI is a potent inhibitor of HIV replication through multiple mechanisms, including blocking viral entry and inhibiting reverse transcriptase.
- Its broad-spectrum activity and efficacy against resistant strains highlight its potential as an anti-HIV therapeutic agent.
- PMTI represents a promising new class of antiviral compounds targeting early stages of HIV infection.