Human immunodeficiency virus (HIV) infects cells after binding of the viral envelope glycoprotein gpl20 to the cell surface recognition marker CD4. gpl20 is noncovalently associated with the HIV transmembrane envelope glycoprotein gp4l, and this complex is believed responsible for the initial stages of HIV infection and cytopathic events in infected cells. Soluble constructs of CD4 that contain the gpl20 binding site inhibit HIV infection in vitro. This is believed to occur by competitive inhibition ofviral binding to cellular CD4. Here we suggest an alternative mechanism of viral inhibition by soluble CD4 proteins. We demonstrate biochemically and morphologically that following binding, the soluble CD4 proteins sT4, VjV2,DT, and V1[106J (amino acids 1-369, 1-183, and -2 to 106 of mature CD4) induced the release of gpl20 from HIV-1 and HIV-1-infected cells. gpl20 release was concentration-, time-, and temperature-dependent. The reaction was biphasic at 37C and did not take place at 4°C, indicating that binding of soluble CD4 was not sufficient to release gp120. The appearance of free gpl20 in the medium after incubation with sT4 correlated with a decrease in envelope glycoprotein spikes on virions and exposure of a previously cryptic epitope near the amino terminus of gp4l on virions and infected cells.

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Incorporating amphotericin B into liposomes was reported to decrease amphotericin B toxicity without a concomitant loss of antifungal efficacy. We formulated an alternative emulsion-based delivery system for amphotericin B and compared it with Fungizone. The maximal tolerated dose (MTD) in mice was 1 mg of Fungizone/kg; however, the MTD was greater than 9 mg of the Intralipid emulsion formulation/kg. The emulsion formulation and Fungizone were equipotent for treating systemic candidiasis in mice. Amphotericin B nephrotoxicity, as manifested by polyuria that was resistant to antidiuretic hormone, was markedly diminished when amphotericin B was administered as an emulsion to rats. Loss of potassium from human red blood cells was also reduced by formulating this agent within emulsions. The emulsion formulation extended the survival time of mice that had established Candida albicans infections, when compared with the Fungizone treatment. The efficacy and reduced toxicity of the amphotericin B emulsion are findings suggesting that the emulsion formulation is preferable to Fungizone.

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