3rd International Workshop on HIV Drug Resistance & Treatment Strategies 23-26 June 1999, San Diego, California, USA

HIV-1 RESISTANCE TO BINDING/FUSION INHIBITORS

Antiviral Therapy 1999;4 (Suppl 1):7 (abstract no. 9)

JA Esté¹ and E De Clercq^2
1IrsiCaixa, Retrovirology Laboratory, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; and ²Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

The replicative cycle of HIV can be interrupted at several stages. The reverse transcriptase (RT) and protease are the enzymes currently targeted by approved antiretroviral agents. However, a number of compounds are being developed that are targeted at earlier stages of infection, namely HIV adsorption (binding) to the host cells and virus–cell fusion. The discovery of chemokine receptors as cofactors for HIV entry has also prompted the development of chemokines and chemokine analogues as anti-HIV agents. Here, we provide an updated account on those binding/fusion inhibitors that are currently considered as potential therapeutic agents and/or for which HIV drug resistance has been studied: the bicyclams AMD3100 and AMD2763, the G-quartet oligonucleotide zintevir, the negatively charged albumins aco-HSA and suc-HSA, dextran sulphate, the chemokine SDF-1α, the fusion inhibitors siamycin, amphotericin B derivative MS8209 and pentafuside T-20. The drug-resistant virus strains recovered from sequential passaging of HIV-1 in the presence of each of these compounds showed multiple mutations in the env gene. The AMD3100-resistant strain proved cross-resistant to polyanions such as dextran sulphate and to chemokine SDF-1α, suggesting that alterations in the gp120 of the AMD3100-resistant virus affect both virus binding to CD4 and chemokine receptor-dependent virus entry. Indeed, mutations found in the dextran sulphate-resistant or zintevir-resistant strains were also found in the AMD3100-resistant strains. Conversely, the AMD3100-resistant virus also had mutations that were not found in the polyanion-resistant strains but were found in the SDF-1α-resistant mutant. Furthermore, addition of AMD3100 to peripheral blood mononuclear cells from infected individuals, displaying the syncytium-inducing phenotype, resulted in a complete phenotypical switch and a concomitant genotype change in the gp120 protein. The development of resistance towards anti-HIV agents that induce changes in the env gene may alter the pathogenicity of the infecting virus.

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