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Session 58 Poster Session Entry Inhibitors Session Time: 4:30-6:30 pm Room 4E-F

395-T. In Vivo Evolution of X4 HIV-1 Variants in the Natural Course of Infection Coincides with Reduced Sensitivity to CXCR4 Antagonists R. P. van Rij1, J. A. Visser1, M. Naarding1, D. Schols2 , and H. Schuitemaker*1 1CLB-Sanquin and Landsteiner Lab., Academic Med. Ctr., Univ. of Amsterdam, The Netherlands; and 2Rega Inst., Leuven, Belgium Background: Antagonists directed against the chemokine receptor CXCR4, the co-receptor for entry of syncytium-inducing (SI) HIV-1 into CD4+ cells, are successful inhibitors of SI HIV-1 infection in vitro and are considered for use as therapeutic drugs. We previously showed that early after their emergence in vivo, SI HIV-1 evolve from a R5X4 phenotype, able to use both CCR5 and CXCR4 in transfected cell lines, to a CXCR4 restricted phenotype (X4 variants). Here, we studied the impact of this evolution on the sensitivity to inhibition with a range of CXCR4 antagonists. Methods: SI HIV-1 biological clones that were isolated just after their first appearance in 2 patients and SI HIV-1 biological clones obtained at later time points from the same patients, were compared for their sensitivity to CXCR4 directed monoclonal antibodies and 2 synthetic compounds, AMD3100 and T22. As a co-receptor independent control sensitivity to gp41 C34 peptide was tested. Results: Late stage X4 variants were less sensitive to inhibition with CXCR4 antagonists than early R5X4 variants from the same patient. IC50 values for late stage SI HIV-1 were comparable to values previously obtained for AMD3100 resistant virus clones that were selected during multiple in vitro passages in the MT2 cell line in the presence of the drug. Surprisingly, even on PBMC, where CCR5 is available as a co-receptor, replication of R5X4 variants was fully inhibited by CXCR4 antagonists and was unaffected by beta chemokines. This indicates that co-receptor usage in transfected U87 cell lines does not necessarily reflect co-receptor usage in primary T cells. Early and late X4 HIV-1 clones showed no significant differences for gp41 C34 peptide neutralization sensitivity. Conclusions: The increasing resistance of X4 variants for CXCR4 antagonists in the natural course of HIV-1 infection may reflect an increasing coreceptor affinity. Our observations may have major implications for the use of chemokine receptor antagonists in antiretroviral therapy regimens.

©2002 9th Conference on Retroviruses and Opportunistic Infections