Viruses are major pathogens in humans, and in the organisms with which we share this planet. The massive health and economic burden these agents impose has spurred a huge research effort to understand their most intimate details. One outcome of this effort has been the production, in many but certainly not all cases, of effective vaccines and therapies. - other consequence has been the realization that we can exploit viruses and put them to work on our behalf. Viruses are still seen to have the most - tential as vehicles for gene delivery and other therapeutic applications. However, their ability to exploit cellular functions to their own ends makes viruses not only highly effective pathogens but also exquisite experimental tools. Work with viruses underpins much of our current understanding of molecular cell biology and related fields. For membrane traffic in parti- lar, viruses have been crucial in providing insights into key cellular fu- tions and the molecular mechanisms underlying these events.

Viral Fusion Mechanisms presents the first comprehensive review on this exciting topic. The book focuses on molecular mechanisms rather than phenomonology and examines a wide range of viruses, including influenza, HIV, Sendai, SFV, Vaccinia, VSV, and RSV. Recent theoretical work on dissecting protein-mediated membrane fusion is discussed, and the most promising new technologies for elucidating mechanisms are highlighted. Viral Fusion Mechanisms is an essential reference for biophysicists, cell biologists, colloid chemists, immunologists, microbiologists, molecular biologists, and virologists.

Protein-mediated membrane fusion is a highly regulated biological process essential for cellular and organismal functions and infection by enveloped viruses. During viral entry, the membrane fusion reaction is catalyzed by specialized protein machinery on the viral surface. These viral fusion proteins undergo a series of dramatic structural changes during membrane fusion where they engage, remodel, and ultimately fuse with the host membrane. The structural and dynamic nature of these conformational changes and their impact on the membranes have long-eluded characterization. Furthermore, the native pre-fusion structural and conformational dynamics of these fusion machines remains unclear as the conventional structural approaches employed by structural biologists are not well suited for studying these dynamic protein machines on the viral surface. The objective of this dissertation is to characterize the complete mechanism of Influenza virus hemagglutinin (HA) fusion activation and membrane fusion, and to profile and characterize the structural and conformational dynamics of the HIV-1 Env fusion glycoprotein on the viral surface. In chapter 2 I use continuous labeling HDX-MS to characterize the structural dynamics and conformational homogeneity of the HIV-1 Env fusion glycoprotein on the surface of two distinct engineered and authentic viral vaccine platforms. By HDX-MS we observed significant amounts of non-native Env present in one vaccine platform, whereas all Env present in the other resembled trimeric Env in the closed conformation. In chapter 3, I use pulse labeling HDX-MS to characterize the mechanism of HA fusion activation and HA mediated membrane fusion in situ using whole infectious virions. Our data reveal how concurrent reorganizations at the HA1 receptor binding domain interface and HA2 fusion subunit produce a dynamic fusion intermediate ensemble in full-length HA. In contrast, the soluble HA ectodomain transitions directly to the post-fusion state with no observable intermediate. These data provide unprecedented insight into the structural mechanics of HA which has served as the prototypical class 1 viral fusion protein and informed our understanding about how all class 1 viral fusion proteins function. In chapter 4 I present developments and improvements on the HDX-MS workflows that will enable more complete characterizations of HA's mechanism and the structural and conformational dynamics of other class 1 viral fusion proteins. Together these works have dramatically furthered our understanding of the structural mechanics of class 1 fusion proteins and lay the foundation for future studies on influenza virus and other enveloped viruses and their membrane fusion machinery.

Membrane fusion and targeting processes are tightly regulated and coordinated. Dozens of proteins, originating from both the cytoplasm and membranes are involved. The discovery of homologous proteins from yeast to neurons validates a unified view. Although much is known about the interfering proteins, the events occurring when two lipid bilayers actually fuse are less clear. It should be remembered that lipid bilayers behave like soap-bubbles fusing when meeting each other. In this respect interfering proteins should be considered as preventing undesirable and unnecessary fusion and eventually directing the biological membrane fusion process (when, where, how, and overcoming the activation energy). In this latest volume in the renowned Subcellular Biochemistry series, some aspects of fusion of biological membranes as well as related problems are presented. Although not complete, there is a lot of recent information including on virus-induced membrane fusion. The contributors of the chapters are all among the researchers who performed many of the pioneering studies in the field.

"Principles of Molecular Virology, Fourth Edition" provides an essential introduction to modern virology in a clear and concise manner. It is a highly enjoyable and readable text with numerous illustrations that enhance the reader's understanding of important principles. It contains new material on virus structure, virus evolution, zoonoses, bushmeat, SARS and bioterrorism. The standard version includes a CD-ROM with Flash animations, virtual interactive tutorials and experiments, self-assessment questions, useful online resources, along with the glossary, classification of subcellular infectious agents and history of virology.