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. 1996 May;70(5):2825–2831. doi: 10.1128/jvi.70.5.2825-2831.1996

Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions.

W A O'Brien 1, M Sumner-Smith 1, S H Mao 1, S Sadeghi 1, J Q Zhao 1, I S Chen 1
PMCID: PMC190139  PMID: 8627756

Abstract

An oligocationic peptide compound (ALX40-4C) was developed for consideration in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This compound was designed to mimic the basic domain of the HIV-1 transactivation protein, Tat, and will competitively inhibit Tat binding to its specific RNA hairpin target (TAR [transactivation region]), found at the 5' end of all HIV-1 transcripts. Blocking Tat-TAR interactions can abrogate HIV-1 replication. ALX40-4C was shown to inhibit replication of HIV-1NL4-3 in a range of cell types, including primary cells and transformed cell lines, by as much as 10(4)-fold. In some experiments, virus rescue was not possible even after removal of ALX40-4C from the cultures. Strain-dependent resistance has been demonstrated for all antiretroviral agents tested; therefore, we tested for variable sensitivity to ALX40-4C. The cloned primary strains, HIV-JR-CSF and HIV-JR-FL, were less sensitive to ALX40-4C inhibition. Unexpectedly, determinants for efficient ALX40-4C inhibition were mapped by using recombinant virus strains to the V3 region of gpl20 and were shown to act at early events in viral replication, which include viral entry. If entry and reverse transcription are bypassed by transfection, a more modest, virus strain-independent inhibition is shown; this inhibition is likely due to blocking of Tat-TAR interaction. Thus, the highly basic oligocationic Tat inhibitor ALX40-4C appears to interfere with initial virus-target cell interactions which involve HIV-1 gp120 V3 determinants, most efficiently for T-cell line-adapted strains.

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Selected References

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