| Research Abstract |
1) The chemokine receptors, CXCR4 and CCR5, are considered to be potential targets for the inhibition of HIV-1 replication. Synthetic peptides, T134 and T140, inhibited X4 HIV-1 infection specifically because they acted as CXCR4 antagonists. To clarify the mechanisms of action of CXCR4 antagonists, we generated T134-resistant HIV (trHIV-1NL4-3) in a cell culture with gradually increasing concentrations of T134. Anti-HIV activities of several CXCR4 antagonists, SDF-1 and v MIP II which coded in KSHV/HHV8 as a chemokine like peptide, were evaluated by MTT assay and MAGI assay. The effects of high concentrations of CXCR4 antagonists against R5 HIV-1 were also investigated. Amino acids mutations of trHIV-1NL4-3 glycoprotein region were sequenced and cross resistancies of other anti-HIV compounds against trHIV-1NL4-3 were studied. As the results, high concentrations of CXCR4 antagonists increased the CCR5 expression and R5 HIV-1 infectivity as did SDF-1. CXCR4 antagonists and SDF-1 also inc
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reased NF-kB activity and viral transcription in the treated cells. The t trHIV-1NL4-3 reduced 15-fold less and also reduced sensitivities against other CXCR4 antagonists, T140, AMD3100 and ALX40-4C, and SDF-1. However, vMIP II which could inhibit both X4 and R5 HIV-1 infection, was still sensitive against trHIMV-1NL4-3. Neither ligands of CCR5, RANTES and MIP-1α, nor a CCR5 low molecular antagonist, TAK-779, were able to influence the infection of trHIV-1NL4-3. The trHIV-1NL4-3 contained several mutations in the not only V3 loop but also V1, V2 and V4 domains of gp120. Thus, resistance to T134 may be conferred by amino acid substitutions in the envelope glycoprotein of X4 HIV-1.
2) The coculture of oral epithelial cells and TPA stimulate HHV8 integrated BCBL-1 cells were carried out and the observed under microscopically. HHV8 genomic DNA and mRNA were also investigated by a PCR method. The cytopathogenic effects were observed in cultured cells but no evidence of HHV8 infection in epithelial cells were detected. Less
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