ABSTRACT:
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 and 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-HAS and suc-HAS, dextran sulfate, the chemokine SDF-1a, 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. AMD3100-reistant strain proved cross-resistant to polyanions such as dextran sulfate and to chemokine SDF-1a, suggesting that alteration in the gp120 of the AMD3100-resistant virus affect both virus binding to CD4 and chemokine receptor-dependent entry. Indeed, mutations found in the dextran sulfate-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-1a-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.
