Dissecting HIV Fusion: Identifying Novel Targets for Entry Inhibitors

Significant momentum has been recently generated in understanding the HIV fusion process. This has led to the development of a host of HIV entry inhibitors which are currently in preclinical and/or clinical development or have been approved for clinical use. In this review we update our understanding of HIV fusion, specifically highlighting novel mechanisms and agents that inhibit this process. Major focus will be placed on three key areas. Initially viral attachment will be reviewed as recent developments in this field emphasize the importance of understanding cell type specific interactions with HIV. This has aided in identifying promising targets for the development of attachment inhibitors. Secondly, we will review the role of cellular lipids in HIV entry. Glycosphingolipids have been shown to interact with different components of the HIV fusion machinery and agents that perturb glycosphingolipid biosynthesis have inhibitory effects on HIV fusion. Likewise, manipulating ceramide biosynthesis also inhibits HIV fusion. Here, we describe how manipulating cellular lipids inhibits HIV fusion and how lipid biosynthesis can be modulated to potentially prevent HIV infection. We end this review by discussing the notion of targeting select host cell proteins for HIV therapy. We will review the role of the cellular proteins PDI, defensins and cytoskeletal proteins in facilitating the fusion reaction. As our understanding of the HIV fusion process increases, the identification of targets for developing entry inhibitors becomes more diverse. Given the rapid resistance of HIV to any selective pressure this is an important avenue in the advancement of drug therapy.