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One family of viruses is responsible for the infection of many species of vertebrates. These are the retroviruses whose genomic RNA is used to support genetic information and ensures many essential functions that are required for the formation of an infectious viral particle. These functions depend on structures formed by the folding of the genomic RNA. Structures and Functions of Retroviral RNAs describes the formation of these structures and their specific interactions with nucleic acids and proteins. In light of recent advances in molecular virology, it provides an understanding of the various facets of the retroviral genome. It emphasizes in particular that the study of the structure–function relationship of retroviral RNAs is a driving force behind increased research into HIV-1, the main causal agent of AIDS. Indeed, one of the challenges of pharmacology lies in the exploitation of several targets which allow us to anticipate and stem the emergence of resistance to anti-HIV drugs. The book also presents structures and interactions that may be potential future targets in this regard.
The first book to specifically cover the molecular biology of retroviruses - of immense importance since the high profile of HIV. International contributors provide detailed reviews of the latest knowledge. An excellent text for both medical and non-medical researchers, it also serves as an illuminating introduction for scientists active in other areas.
Virus Structure covers the full spectrum of modern structural virology. Its goal is to describe the means for defining moderate to high resolution structures and the basic principles that have emerged from these studies. Among the topics covered are Hybrid Vigor, Structural Folds of Viral Proteins, Virus Particle Dynamics, Viral Gemone Organization, Enveloped Viruses and Large Viruses. Covers viral assembly using heterologous expression systems and cell extracts Discusses molecular mechanisms in bacteriophage T7 procapsid assembly, maturation and DNA containment Includes information on structural studies on antibody/virus complexes
For over 25 years the study of retroviruses has underpinned much of what is known about information transfer in cells and the genetic and biochemical mechanisms that underlie cell growth and cancer induction. Emergent diseases such as AIDS and adult T-cell lymphoma have widened even further the community of investigators directly concerned with retroviruses, a development that has highlighted the need for an integrated understanding of their biology and their unique association with host genomes. This remarkable volume satisfies that need. Written by a group of the field's most distinguished investigators, rigorously edited to provide a seamless narrative, and elegantly designed for clarity and readability, this book is an instant classic that demands attention from scientists and physicians studying retroviruses and the disorders in which they play a role.
Among the first diseases for which a viral etiology was esta- blished were tumors, lymphomas, and sarcomas in chickens, shown by Ellermann and Bang (1908) and Rous (1910) to be transmissible with cell-free filtrates. The broad significance of these discoveries was not fully recognized at first, mainly because chickens were perceived as too distanly related to humans to provide useful and relevant models for human disease. Change came slowly. In 1936 Bittner found that a viral agent is involved in the causation of mammary cancer in mice, and in 1957 Gross discovered the first murine leukemia virus. In the years following numerous tumor-inducing viruses, infecting all classes of verte- brates, were isolated. The decisive impulse for the development of the RNA tumor virus field sprang from advances in cell culture. In 1958 Temin and Rubin, following initial observations of Manaker and Groupe, worked out the conditions for virus-induced tumori- genic transformation in cell culture and made this transform- ation the basis for a quantitative assay of viral infectivity and oncogenicity. The genetic and cell biological studies that grew out of Rubin's and Temin's groundwork quickly brought into focus two puzzling problems: a requirement for DNA synthesis early in the lifecycle of the RNA tumor viruses, and the existence of genetic information in the virus that is needed for oncogenesis but not for virus reproduction.
This book comprehensively covers the mechanisms of action and inhibitor design for HIV-1 integrase. It serves as a resource for scientists facing challenging drug design issues and researchers in antiviral drug discovery. Despite numerous review articles and isolated book chapters dealing with HIV-1 integrase, there has not been a single source for those working to devise anti-AIDS drugs against this promising target. But this book fills that gap and offers a valuable introduction to the field for the interdisciplinary scientists who will need to work together to design drugs that target HIV-1 integrase.
The Subcellular Biochemistry series has recently embarked upon an almost encyclopaedic coverage of topics relating to the structure and function of macromolecular complexes (Volumes 82, 83 and 87). The present multi-author text covers numerous aspects of current research into molecular virology, with emphasis upon viral protein and nucleoprotein structure and function. Structural data from cryo-electron microscopy and X-ray crystallography is displayed throughout the book. The 17 chapters in the book cover diverse interesting topics, all currently under investigation, contributed by authors who are active actively involved in present-day research. Whilst structural aspects predominate, there is much consideration of the structure-function relationship. In addition, the book correlates with and extends from Volume 68 of the series “Structure and Physics of Viruses: An Integrated Textbook”. This book is directed primarily at professionals that work in the broad field of Structural Biology and will be of particular interest to Structural Virologists. The editors, David Bhella and Robin Harris, have much experience in virology and protein structure, respectively. Dr Bhella is Director of the Scottish Macromolecular Imaging Centre. Professor Robin Harris is the long-standing Series Editor of the Subcellular Biochemistry series. He has edited and contributed to several books in the series.
One family of viruses is responsible for the infection of many species of vertebrates. These are the retroviruses whose genomic RNA is used to support genetic information and ensures many essential functions that are required for the formation of an infectious viral particle. These functions depend on structures formed by the folding of the genomic RNA. Structures and Functions of Retroviral RNAs describes the formation of these structures and their specific interactions with nucleic acids and proteins. In light of recent advances in molecular virology, it provides an understanding of the various facets of the retroviral genome. It emphasizes in particular that the study of the structure–function relationship of retroviral RNAs is a driving force behind increased research into HIV-1, the main causal agent of AIDS. Indeed, one of the challenges of pharmacology lies in the exploitation of several targets which allow us to anticipate and stem the emergence of resistance to anti-HIV drugs. The book also presents structures and interactions that may be potential future targets in this regard.
HIV-1, a single-stranded RNA retrovirus, has devastated millions of people worldwide. Understanding how this virus infects cells and replicates is critical for both understanding retroviruses and making next generation antiretrovirals that can improve quality of life for people living with HIV. While decades of research have been dedicated to the understanding of this virus, key mechanistic information remains to be elucidated. RNA structure plays a key role in regulating different stages of the HIV replication cycle. HIV-1 genomic RNA contains a highly structured and conserved 5' untranslated region that is the hub for multiple functions during viral replication. Reverse transcription, the process by which HIV converts its single-stranded RNA genome into double-stranded DNA, represents an early stage in the virus' replication cycle where the viral genome is simultaneously copied and prepared for integration into the host cell's genome. Translation of the genomic RNA transcripts allows production of the proteins that comprise new HIV virions. Both processes initiate in the 5' UTR region of the genomic RNA. There are many open questions surrounding mechanism, efficiency, and kinetics of these processes due to the structural and functional density of the 5'UTR. Furthermore, many conserved structures and RNA interactions that have been demonstrated to be important in cell cultures have yet to be placed within the context of viral replication processes. Here I present my thesis work to understand how RNA structure in this region of the viral genome regulates reverse transcription and translation initiation. Reverse transcription begins upon entry of a viral capsid into a host cell cytoplasm. The process can be divided into initiation and elongation phases. The initiation phase is very slow and non-processive while the elongation phase is quite rapid and processive. To understand why the initiation phase is so slow, a minimal construct was crosslinked to reverse transcriptase (RT) and purified for cryogenic electron microscopy (cryoEM). The complexes captured a reverse transcription initiation complex (RTIC) after three and six rounds of incorporation. The +3 RTIC represents a significant stalling point for the process, with an approximately 10- fold decrease in rate compared to the other steps in the initiation phase. The +6 RTIC represents the transition from the slow, non-processive initiation phase to elongation phase. The resulting data showed conformational heterogeneity after three rounds of incorporation. This heterogeneity showed intermediate states that represent off-pathway intermediates that are the result of a stable hairpin in the templating viral RNA. After six rounds of incorporation, the complex shows novel RNA density corresponding to a previously demonstrated regulatory RNA interaction. Additionally, the primer terminus is poised for catalysis, relative to previous RTIC structures. These structural changes are likely responsible for the steep rise in processivity, and speed observed after 6 rounds of dNTP incorporation. In the latter phase of viral replication, viral proteins and genomic RNA must be assembled into virions and bud from the cell. To achieve this, viral mRNAs are transcribed from HIV genes and host cell ribosomes are used to make viral factors. However, the mechanisms used to initiate translation of HIV proteins required for viral assembly and budding remain poorly defined. Here we focused on the regulatory role of the 5'UTR structure and sequence in HIV mRNA translation initiation. To understand how HIV translation initiation differs from standard translation initiation, the 5'UTR was cloned in front of a nano luciferase (nLuc) luminescence reporter gene. The bulk translation activity of the resulting mRNA was assayed in HeLa cell extracts. RNAs containing the HIV 5'UTR had a significant drop in translation efficiency. While they translate poorly relative to housekeeping genes, there is no significant difference between the translation efficiency, mean synthesis rate, and mean synthesis time for capped and uncapped HIV mRNAs. Using single-molecule fluorescence to track translation components during initiation, the kinetics of translation initiation for the housekeeping gene control and the HIV mRNA constructs were similar, however, the small ribosomal subunit struggles to load onto the structured 5'-UTR. This results in most small ribosomal subunit binding events not leading to successful translation initiation for HIV mRNAs. Together, these findings provide evidence for RNA structure as playing a regulatory role in translation initiation. This inefficiency might be advantageous for the virus to maintain a slow yet steady pace for virion assembly such that it minimally triggers immune system sensors.