Background: Significant rates of therapeutic failure have been reported due to the emergence of HIV strains resistant to one or more of the classes of antiretrovirals used in HAART therapy, demonstrating the need for new classes of drugs. Viral entry, which occurs through a series of complex steps involving interaction with at least 2 cellular receptors prior to fusion of the viral and cellular membranes, provides an excellent source of targets for the development of new classes of inhibitors. 

Methods: Using a cell-based screen, a novel, small molecule HIV-1 inhibitor was identified that targets the HIV envelope protein and blocks the entry of virus into cells. 

Results: The HIV entry inhibitor is effective against macrophage-, T-, and dual-tropic HIV-1 laboratory strains, and is a potent inhibitor of  HIV-1 clinical isolates, displaying a median EC₅₀ of 62 nM in culture assays against clade B isolates.  This new class of inhibitors is selective for HIV-1, showing no significant activity against HIV-2, SIV, and a panel of unrelated viruses.  The entry inhibitor exhibited no significant cytotoxicity in the 13 cell types tested (CC₅₀ >225 μM) and its anti-HIV potency is impacted negligibly by the presence of human serum.  Oral bioavailability was demonstrated in 3 animal species and no safety concerns were identified in initial animal toxicology studies. As expected, HIV-1 variants resistant to inhibitors of the reverse transcriptase and protease retained full sensitivity to the entry inhibitors.  In vitro passage of either T-tropic or M-tropic HIV-1 strains in the presence of the inhibitors selected for drug resistant virus variants.  Genotypic analysis of these resistant viruses indicated that the selected mutations were predominantly located within either gp41 or at/near the CD4-binding segments of gp120, indicating that the HIV-1 envelope glycoproteins are the likely targets.  Recombinant viruses containing these amino acid changes also displayed phenotypic resistance to the entry inhibitors. 

Conclusions: The entry inhibitors described here are distinct from the CCR-5 and fusion inhibitors described by others.  The encouraging preclinical profile of this novel inhibitor and its potential utility in all patient populations warrants further evaluation.