Dissecting HIV Fusion: Identifying Novel Targets for Entry Inhibitors

Abstract

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.

A Novel Receptor-induced Activation Site in the Nipah Virus Attachment Glycoprotein (G) Involved in Triggering the Fusion Glycoprotein (F)

“…This is exemplified by CD4-induced coreceptor binding epitopes in HIV gp120. Binding to coreceptor after CD4-induced conformational changes in HIV gp120 triggers fusion peptide exposure in gp41 and the subsequent six-helix bundle formation that eventually leads to membrane fusion (23,24). NiV also uses a protein-based receptor and a type I fusion protein, although in this Paramyxovirus, the receptor-interacting attachment glycoprotein (G) is physically distinct from the fusion (F) protein.…”

The metabolism and function of sphingolipids and glycosphingolipids

“…Other pathogens exploit the SLs of host cells as membrane receptors. For example, sialic acid on gangliosides is involved in influenza virus internalization [174], and different components of the HIV fusion machinery interact with cell surface GSLs [175]. As a consequence, binding of some pathogens and toxins to human cells can be prevented by depleting host cells of their surface GSLs or by coating the binding sites of pathogens with GSL-like substances that compete with the pathogen for binding [176].…”

Glycosphingolipids in HIV/AIDS: The Potential Therapeutic Application

“…Several studies have investigated cholesterol-depletion as a means of disrupting lipid rafts to prevent HIV-1 fusion and entry (Liao et al, 2001;Liao et al, 2003) It has also been proposed that increasing ceramide levels in CD4 + lymphocytes and monocyte-derived macrophages may block HIV infection, perhaps inhibiting HIV fusion by disrupting normal lipid raft organization and function (Finnegan & Blumenthal, 2006).These studies have used several mechanisms to increase ceramide, including pharmacological agents, such as N-(4-hydroxyphenyl) retinamide and fenretinide, treatment with sphingomyelinase or addition of long-chain ceramide. Lipid-raft altering compounds may have dual efficacy in treatment of HIV/AIDS.…”