CALMODULIN ANTAGONISTS INHIBIT HUMAN IMMUNODEFICIENCY VIRUS-INDUCED CELL-FUSION BUT NOT VIRUS-REPLICATION

We have reported that amphipathic helical segments in the cytoplasmic domain of the HIV-1 envelope glycoproteins bind to calmodulin (CaM) wi th high affinity, and inhibit calmodulin-regulated proteins. To invest igate the possible role of calmodulin activity in HIV-1 replication, w e investigated the anti-HIV activity of various CaM antagonists-triflu operazine and naphthalenesulfonamide W13 or W7-in HeLa T4 cells, PBMCs , and various T lymphocytic cell lines. The different CaM antagonists were found to inhibit the proliferation of the different cell types to varying extent. Also, the CaM antagonists were found to exert a great er antiproliferative effect on H9/HIV-1(IIIB), as compared to uninfect ed H9 cells, suggesting a deficit of CaM function in HIV-infected cell s. The CaM antagonists inhibited virus-induced cell fusion in HeLa T4 cells infected with a recombinant vaccinia virus expressing HIV-1 enve lope proteins at threshold concentrations that do not inhibit cell pro liferation. The fusion-inhibitory effects of the CaM antagonists were also observed in cocultures of HIV-infected (H9/HIV-1(IIIB)) and uninf ected H9 cells. Under these conditions, the synthesis and surface expr ession of the viral glycoproteins were not affected, although the kine tics of processing of HIV envelope precursor was delayed. Virus produc tion from both HIV-infected peripheral blood mononuclear cell (PBMC) a nd MT-2 cell cultures was inhibited by CaM antagonists at concentratio ns that were inhibitory to cell proliferation. Surprisingly, threshold concentrations of CaM antagonists that do not inhibit cell proliferat ion were found to enhance virus production from HIV-infected MT-2 cell s, but not PBMCs. These results suggest that intracellular CaM may reg ulate the extent of virus replication and cytopathology in HIV-infecte d cells.