T30177, an oligonucleotide composed of only deoxyguanosine and thymidine, is 17 nucleotides in length and contains single phosphorothioate internucleoside linkages at its 5 and 3 ends for stability. This oligonucleotide does not share significant primary sequence homology with or possess any complementary (antisense) sequence motifs to the human immunodeficiency virus type 1 (HIV-1) genome. T30177 inhibited replication of multiple laboratory strains of HIV-1 in human T-cell lines, peripheral blood lymphocytes, and macrophages. T30177 was also found to be capable of inhibiting multiple clinical isolates of HIV-1 and preventing the cytopathic effect of HIV-1 in primary CD4 ؉ T lymphocytes. In assays with human peripheral blood lymphocytes there was no observable toxicity associated with T30177 at the highest concentration tested (100 M), while the median inhibitory concentration was determined to be in the range of 0.1 to 1.0 M for the clinical isolates tested, resulting in a high therapeutic index for this drug. In temporal studies, the kinetics of addition of T30177 to infected cell cultures indicated that, like the known viral adsorption blocking agents dextran sulfate and Chicago sky blue, T30177 needed to be added to cells during or very soon after viral infection. However, analysis of nucleic acids extracted at 12 h postinfection from cells treated with T30177 at the time of virus infection established the presence of unintegrated viral cDNA, including circular proviral DNA, in the treated cells. In vitro analysis of viral enzymes revealed that T30177 was a potent inhibitor of HIV-1 integrase, reducing enzymatic activity by 50% at concentrations in the range of 0.050 to 0.09 M. T30177 was also able to inhibit viral reverse transcriptase activity; however, the 50% inhibitory value obtained was in the range of 1 to 10 M, depending on the template used in the enzymatic assay. No observable inhibition of viral protease was detected at the highest concentration of T30177 used (10 M). In experiments in which T30177 was removed from infected cell cultures at 4 days post-HIV-1 infection, total suppression of virus production was observed for more than 27 days. PCR analysis of DNA extracted from cells treated in this fashion was unable to detect the presence of viral DNA 11 days after removal of the drug from the infected cell cultures. The ability of T30177 to inhibit both laboratory and clinical isolates of HIV-1 and the experimental data which suggest that T30177 represents a novel class of integrase inhibitors indicate that this compound is a viable candidate for evaluation as a therapeutic agent against HIV-1 in humans.One relatively new approach used in the development of antiviral therapeutics for human immunodeficiency virus type 1 (HIV-1) is the use of oligonucleotides designed as antisense agents (24,26,31). While much effort is being spent on rationally designed oligonucleotides such as antisense agents, there have also been recent findings of multiple alternative mechanisms by which oligonucleotides can i...

A galactan sulfate (GS) was isolated from an aqueous extract of the red seaweed Aghardhiella tenera and partially purified. GS inhibited the cytopathic effect of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in MT-4 cells at concentrations 10-fold higher than those required for the inhibition by dextran sulfate (MW 5000) of the cytopathic effect of HIV-1 and HIV-2 (50% inhibitory concentrations: 0.5 and 0.05119 mr", respectively). GS suppressed syncytium formation between MOLT-4 cells and persistently HIV-1-or HIV-2-infected HUT-78 cells at concentrations higher than 5119 mr". Like dextran sulfate (OS) and aurintricarboxylic acid (ATA), GS inhibited the binding of HIV-1 to the cells and the binding of anti-gp120 mAb to HIV-1 gp120. Like OS and ATA, GS proved active not only against HIV-1 and HIV-2 but also against other enveloped viruses, l.e, herpes-, toga-, arena-, myxo-and rhabdoviruses. GS represents a natural polysaccharide with broad-spectrum activity against a number of important viral pathogens.

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