Anti-HIV type 1 activity of sulfated derivatives of dextrin against primary viral isolates of HIV type 1 in lymphocytes and monocyte-derived macrophages.

The anti-HIV-1 activity of sulfated derivatives of dextrin was tested in activated peripheral blood mononuclear cells and in monocyte-derived macrophages using low-passage syncytium-inducing and non-syncytium-inducing primary viral isolates of HIV-1. All four compounds blocked infection in a dose-dependent manner. Dextrin 2-sulfate blocked infection with a 90% inhibitory concentration (IC90) of 69 microg ml(-1). The IC90 for dextrin 3-sulfate was 50 microg ml(-1) and for dextrin 6-sulfate was 14 microg ml(-1). Increasing the number of sulfate groups to three per glucan molecule (dextrin 2-, 3-, and 6-sulfate) did not reduce the IC90 further (13 microg ml(-1)) compared to dextrin 6-sulfate. There was no significant difference in the concentration required to block infection of activated peripheral blood mononuclear cells when compared with monocyte-derived macrophages, irrespective of whether low-passage syncytium-inducing or non-syncytium-inducing primary viral isolates of HIV-1 were used. Dextrin 2-sulfate and dextrin 6-sulfate also reduced the transmission of HIV-1 in experiments performed using peripheral blood mononuclear cells from HIV-1-positive patients by 6- to 251-fold in a limiting dilution tissue culture infectious dose assay. Sulfated dextrins were not toxic to either primary lymphocytes or macrophages at the concentrations tested. Having previously shown that the cell surface binding of sulfated dextrins is dependent on the position of the negatively charged sulfate groups, we now show that their anti-HIV-1 activity in primary lymphocytes and macrophages is also dependent on the same arrangement. A phase I/II clinical trial of dextrin 2-sulfate is now in progress.

Infection by HIV-1 blocked by binding of dextrin 2-sulphate to the cell surface of activated human peripheral blood mononuclear cells and cultured T-cells.

1. Structural analogues of a sulphated polysaccharide, dextrin sulphate, were synthesized and tested for their ability to block infection by HIV-1. Using the T-cell lines, C8166 and HPB-ALL, and the laboratory adapted strains of HIV-1.MN, HIV-1.IIIb and HIV-1.RF, dextrin 2-sulphate (D2S) combined the best combination of high anti-HIV-1 activity (95% inhibitory concentration (IC95) = 230 nM) and low anticoagulant activity. It also blocked infection of activated peripheral blood mononuclear (PBMN) cells by five primary viral isolates at an IC95 of 230-3700 nM depending upon the primary viral isolate tested. 2. In saturation binding studies, [3H]-D2S bound to a cell surface protein on HPB-ALL cells in a specific and saturable manner with a Kd of 82 +/- 14 nM and a Bmax of 4.8 +/- 0.3 pmol/10(6) cells. It bound to other human T-cell lines in a similar manner. 3. There was very little binding of [3H]-D2S to freshly isolated PBMN cells (Bmax 0.18 +/- 0.03 pmol/10(6) cells) and these cells could not be infected by HIV-1. Culture of PBMN cells in lymphocyte growth medium (LGM) containing IL-2 did not significantly change the Bmax of [3H]-D2S. In contrast, PBMN cells which had been cultured with phytohaemagglutinin (PHA; 5 micrograms ml-1) for 72 h had a Bmax of [3H]-D2S binding of 7.2 +/- 0.1 pmol/10(6) cells and these cells could be infected by HIV-1. Removal of the PHA and further culture of the PBMN cells in LGM containing IL-2 resulted in a fall in the Bmax to 2.0 +/- 0.1 pmol/10(6) cells. The Kd of binding did not change significantly during the course of these experiments.4. [3H]-D2S did not bind to freshly isolated erythrocytes or to erythrocytes which had been cultured in PHA for 72 h.5. These results suggest that there is a relationship between the expression of the [3H]-D2S binding protein on the plasma membrane of PBMN cells and the susceptibility of these cells to infection by HIV- 1.