Resistance Against Inhibitors of HIV-1 Entry into Target Cells

HIV resistance against currently approved entry inhibitors, the chemokine receptor-5 (CCR5) antagonist maraviroc and the fusion inhibitor enfuvirtide (T-20), manifests in a complex manner that is distinct from the resistance patterns against other classes of antiretroviral drugs. Several attachment and fusion inhibitors are currently under various stages of development. Whereas CCR5 co-receptor antagonists have been widely studied until now, because patients who lack CCR5 are healthy and protected to some extent from HIV-infection, CXCR4-antagonist development has been slower, due to limited antiviral activity and potential toxicity given that CXCR4 may have essential cellular functions. Novel fusion inhibitor development is focusing on orally available small-molecule inhibitors that might replace T-20, which needs to be administered by subcutaneous injection.