A series of variously substituted diarylsulfones and related derivatives were found to prevent human immunodeficiency virus type 1 (HIV-1) replication and HIV-1-induced cell killing in vitro. One of the more potent derivatives, 2-nitrophenyl phenyl
sulfone (
NPPS), completely protected human CEM-SS lymphoblastoid cells from the cytopathic effects of HIV-1 in cell culture at 1 to 5 microM concentrations. HIV-1 replication, as assessed by the production of infectious virions, viral p24
antigen, and virion
reverse transcriptase (RT), was inhibited by
NPPS at similar concentrations. There was no evidence of direct cytotoxicity of the
drug at concentrations below 100 microM. A variety of other CD4+ T-cell lines as well as cultures of peripheral blood leukocytes and monocytes were protected from HIV-1-induced cytopathicity and/or viral replication.
NPPS also inhibited several distinctly different strains of HIV-1 but was ineffective against three strains of HIV-2. Biochemical studies revealed that
NPPS inhibited HIV-1 RT but not HIV-2 RT.
NPPS had no direct effect on HIV-1 virions, nor did it block the initial binding of HIV-1 to target cells. Time-limited treatments of cells with
NPPS found that
NPPS had to be present continuously in culture to provide maximum
antiviral protection. In addition, HIV-1 replication in cells in which
infection was already fully established or in chronically infected cells was also unaffected by
NPPS. We conclude that
NPPS acts in a reversible manner as a nonnucleoside HIV-1-specific RT inhibitor. Although markedly different in structure from a larger, structurally diverse group of known HIV-1-specific nonnucleoside RT inhibitors,
NPPS shares several of the
biological properties that characterize this emerging new pharmacologic class.