HIV-1 Entry and Fusion Inhibitors: Mechanisms and Resistance

HIV entry research in the mid-1990s made two key discoveries: (1) formation of a unique six-alpha helix bundle in the viral envelope which is necessary for viral-cell membrane fusion and (2) the identification of two key co-receptors, CXCR4 and CCR5, which permit host cell entry of the syncytium- and non-syncytium-inducing HIV-1 strains, respectively. With these discoveries, entry inhibitors represented the most promising class of new antiretrovirals for prevention and treatment of HIV-1 infection. However, after 10 years of research, only enfuvirtide and maraviroc have been approved by the FDA despite hundreds of preclinical candidates, dozens of potential drugs tested in phase I trials, and three phase III trials.