1st International Workshop on HIV Drug Resistance & Treatment Strategies


25-28 June 1997, St. Petersburg, Florida, USA


INTERFERENCE OF HIV ENTRY BY INHIBITING INTERACTIONS WITH CXCR4

Antiviral Therapy 1997;2 (Suppl 5):4 (abstract no. 7)

WA O'Brien1, K Grovit-Ferbas2,4, ES Daar2,3, BJ Doranz5 and RW Doms5
1University of Texas Medical Branch, Galveston, Texas; 2UCLA School of Medicine, Los Angeles, California; 3Cedars-Sinai Medical Center, Los Angeles, California; 4Department of Veterans Affairs, Los Angeles, California; and 5University of Pennsylvania Medical Center, Pittsburgh, Pennsylvania, USA

CD4 is a crucial receptor for HIV infection of primary cells, but recent studies have identified other cell surface molecules that are necessary for efficient HIV entry. These include CXCR4 (also known as fusin or LESTR), which is used by virus strains adapted to growth in transformed T cell lines. These HIV strains, as well as a subset of primary HIV strains, cause syncytium-induction (SI) in MT-2 cells and in primary T cells. A polycationic peptide, ALX40-4C, was previously shown to block entry of T cell line-adapted HIV strains by interfering with interactions between V3 and the target cells. Here we show inhibition of HIV-IIIB-induced fusion in quail cells (QT6) expressing CD4 and CXCR4. To determine whether this inhibition can be generalized to primary HIV strains, we assessed ALX40-4C inhibition of a panel of seven primary SI strains and three non-SI (NSI) strains. Only 2/7 SI strains and 0/3 NSI strains were inhibited by this compound. Sequence analysis of the V3 region of these primary isolates revealed a high net positive charge on the SI strains, similar to that seen with T cell line-adapted strains. These findings support other studies which showed that primary SI strains may utilize CCR5 preferentially, or in addition to CXCR4. Alternatively, the HIV SI isolates may contain quasispecies which exhibit different sensitivities to ALX40-C. Compounds which inhibit CCR5 interactions may suppress replication in a larger subset of primary HIV-1 strains, and prove to be effective therapeutic agents.

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1997-06-25
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