The formation of multinucleated giant cells with progression to cell death is a characteristic manifestation of the cytopathology induced by the AIDS retrovirus in infected T lymphoid cells. The mechanism of giant cell formation was studied in the CD4 (T4/Leu 3) positive T cell lines JM (Jurkat) and VB and in variants of these lines that are negative for cell surface CD4 antigen. By means of a two-color fluorescent labeling technique, multinucleated giant cells in infected cultures were shown to form through cell fusion. Antibody to CD4 specifically inhibited fusion, and uninfected CD4 negative cells, in contrast to uninfected CD4 positive cells, did not undergo fusion with infected cells, suggesting a direct role for the CD4 antigen in the process of syncytium formation. These results suggest that, in vivo, cell fusion involving the CD4 molecule may represent a mechanism whereby uninfected cells can be incorporated into AIDS virus infected syncytia. Because the giant cells die soon after they are formed, this process may contribute to the depletion of helper/inducer T cells characteristically observed in AIDS.

We wanted to establish an in vitro human model for AIDS-associated dementia and pursue the hypothesis that this disease process may be a result of soluble factors produced by HIV-infected macrophages. Human brain aggregates were prepared from nine different brain specimens, and were treated with supernatants from in vitro HIV-infected macrophages (SI), uninfected macrophages (SU), infected T cells, or macrophage-conditioned media from four AIDS patients.Seven of nine treated brains exposed to SI showed periph-

An oligonucleotide (I100-15) composed of only deoxyguanosine and thymidine was able to inhibit human immunodeficiency virus type-1 (HIV-1) in culture assay systems. I100-15 did not block virus entry into cells but did reduce viral-specific transcripts. As assessed by NMR and polyacrylamide gel methods, I100-15 appears to form a structure in which two stacked guanosine tetrads are connected by three two-base long loops. Structure/activity experiments indicated that formation of intramolecular guanosine tetrads was necessary to achieve maximum antiviral activity. The single deoxyguanosine nucleotide present in each loop was found to be extremely important for the overall antiviral activity. The toxicity of I100-15 was determined to be well above the 50% effective dose (ED50) in culture which yielded a high therapeutic index (> 100). The addition of a cholesterol moiety to the 3' terminus of I100-15 (I100-23) reduced the ED50 value to less than 50 nM (from 0.12 microM for I100-15) and increased the duration of viral suppression to greater than 21 days (versus 7-10 days for I100-15) after removal of the drug from infected cell cultures. The favorable therapeutic index of such molecules coupled with the prolonged suppression of HIV-1, suggest that such compounds further warrant investigation as potential therapeutic agents.

No abstract

No abstract