HIV Resistance to Entry Inhibitors

The replicative cycle of HIV can be interrupted at several stages. The reverse transcriptase 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 coreceptors for HIV entry has also prompted the development of chemokines and chemokine analogues as anti-HIV agents. HIV will escape the inhibitory action of entry inhibitors by different mechanisms depending on the mode of action of the specific agent or how the selection of resistant variants was designed. As expected, development of resistance to entry inhibitors is followed by the emergence of mutations in the corresponding gene. Resistance to agents that block virus attachment, virus binding to CD4 and agents that block coreceptor interaction generate HIV strains with mutations in the gp120 coding region. Agents that target gp41-dependent fusion select for HIV variants with mutations in the gp41 gene. Since HIV may use more than one coreceptor for entry, there are HIV strains that are naturally resistant to agents that block a specific coreceptor. Under selection pressure and with an alternative coreceptor available, HIV should switch coreceptor use. Alternatively, HIV may develop resistance to a coreceptor antagonist in the absence of coreceptor switch. Notably, the fact that envelope glycoproteins are key determinants of virus induced pathogenicity, tropism, replicative capacity and viral fitness suggests that mutations that confer resistance to entry inhibitors will modify these parameters.Thus, therapeutic strategies that aim at blocking virus entry may also be used to alter the natural evolution of HIV in an unprecedented way. By altering HIV envelope-dependent pathogenicity, we could envision new ways to manage a chronic virus infection. Results from recent clinical trials with the fusion inhibitor T-20 are encouraging. HIV entry appears to be the next target for therapeutic intervention as new agents that block the early steps of HIV replication are being evaluated in the clinic. New technology for phenotypic and genotypic assessment of drug resistance needs to be in place for the coming of a new generation of antiretroviral agents.