HIV-1 entry inhibitors: closing the front door

Highly active antiretroviral therapy (HAART) has led to major declines in morbidity and mortality of HIV-1-infected individuals, but the increasing prevalence of drug-resistant viral isolates, combined with the toxicity and other limitations of current treatments, make the development of new therapies a high priority. As knowledge of viral entry has expanded, this step of the viral life cycle has become a target for novel therapeutic strategies. An emerging group of antiretrovirals, known collectively as entry inhibitors, targets several distinct steps in viral entry including CD4 binding, chemokine receptor engagement and the structural changes in the viral envelope required for fusion between viral and cellular membranes. Many entry inhibitors are in various stages of clinical development, with one already licensed for use. This review will provide an overview of the mechanisms involved in the entry process, highlight promising entry blockers under development and discuss several considerations related to treatment that are unique to this class of antiretroviral drugs.