Targeting HIV-1 gp41 in close proximity to the membrane using antibody and other molecules

HIV-1 envelope glycoprotein (Env) spikes are supported at the viral membrane interface by a highly conserved and hydrophobic region of gp41, designated the membrane-proximal external region (MPER). The MPER is mandatory for infection of host cells by HIV-1, and is the target of some of the most broadly neutralizing antibodies described to date. As such, the MPER is also of considerable interest for HIV vaccine design. However, structural models indicate that the MPER assumes distinct conformations prior to and leading up to Env-mediated fusion. Thus, the more of these distinct conformations that antibodies and inhibitors can recognize will likely be the better for antiviral potency. In addition to its flexibility, the MPER is lipophilic and its accessibility to bulky macromolecules is limited by steric and kinetic blocks that present particular challenges for eliciting HIV-1 neutralizing antibodies. Moreover, the ability of the MPER and viral membrane to combine as a complex has critical mechanistic implications for molecules that target lipid-bound and/or unbound states. Interestingly, membrane affinity frequently appears to enhance the potency of both fusion inhibitors and antibodies to different sites on gp41. We therefore highlight mechanisms to be harnessed in targeting membraneproximal sites on HIV gp41 for both vaccine and fusion inhibitor design. Such design efforts will likely need to draw upon knowledge of MPER structure and function, and may in turn inform analogous approaches to MPERs of other enveloped viruses and systems.