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A Novel Gene Therapy Approach Based on Secreted Antiviral Proteins for the Control of HIV Replication

A Novel Gene Therapy Approach Based on Secreted Antiviral Proteins for the Control of HIV Replication
Author: Alexander Falkenhagen
Publisher:
Total Pages:
Release: 2017
Genre:
ISBN:

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HIV entry into target cells requires the interaction of the HIV envelope glycoprotein (Env) with a primary receptor (CD4) and a co-receptor (most commonly CCR5 or CXCR4). Protein-based HIV entry inhibitors are highly effective in protecting cells from infection. However, their clinical application is limited because their use requires the frequent injection of highly purified proteins. This study focuses on the development of a gene therapy strategy for the delivery of protein-based HIV entry inhibitors. In Chapter 2 we show that an antibody fragment targeting CCR5 (sscFvPRO140) is secreted from gene-modified human cells and can protect unmodified cells from infection. Chapter 3 describes the secretion and antiviral effect of entry inhibitors targeting HIV Env. A soluble receptor (sCD4), sCD4 covalently linked to a fusion inhibitor (sCD4-FIT45) and sCD4 linked to an antibody fragment targeting the co-receptor-binding site (sCD4-scFv17b) were secreted in significant quantities and protected primary HIV target cells from infection. In Chapter 4 we examine the secretion of sCD4 in a mouse model of HIV infection. sCD4 was present in the blood (~100 ng/ml) of mice engrafted with gene-modified hematopoietic stem cells, reduced viral load over time and protected CD4+ T cells from depletion. Chapter 5 describes the use of gene-modified cell lines for the production of secreted human proteins and their small-scale purification from the culture media. In Chapter 6 we further investigate the antiviral potency of sCD4-FIT45. The bifunctional protein inhibited HIV Env-mediated cell fusion and HIV entry of several primary isolates more potently than VRC01, sCD4, or sCD4-scFv17b. Taken together, we have shown that human cells can be engineered to secrete HIV inhibitors. Furthermore, our results highlight the benefit of combining inhibitors that target receptor-binding and membrane fusion.


Human Herpesviruses

Human Herpesviruses
Author: Ann Arvin
Publisher: Cambridge University Press
Total Pages: 1325
Release: 2007-08-16
Genre: Medical
ISBN: 1139461648

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This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.


Recoding: Expansion of Decoding Rules Enriches Gene Expression

Recoding: Expansion of Decoding Rules Enriches Gene Expression
Author: John F. Atkins
Publisher: Springer Science & Business Media
Total Pages: 473
Release: 2010-03-10
Genre: Science
ISBN: 0387893822

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The literature on recoding is scattered, so this superb book ?lls a need by prov- ing up-to-date, comprehensive, authoritative reviews of the many kinds of recoding phenomena. Between 1961 and 1966 my colleagues and I deciphered the genetic code in Escherichia coli and showed that the genetic code is the same in E. coli, Xenopus laevis, and guinea pig tissues. These results showed that the code has been c- served during evolution and strongly suggested that the code appeared very early during biological evolution, that all forms of life on earth descended from a c- mon ancestor, and thus that all forms of life on this planet are related to one another. The problem of biological time was solved by encoding information in DNA and retrieving the information for each new generation, for it is easier to make a new organism than it is to repair an aging, malfunctioning one. Subsequently, small modi?cations of the standard genetic code were found in certain organisms and in mitochondria. Mitochondrial DNA only encodes about 10–13 proteins, so some modi?cations of the genetic code are tolerated that pr- ably would be lethal if applied to the thousands of kinds of proteins encoded by genomic DNA.


HIV-1 Latency

HIV-1 Latency
Author: Guido Silvestri
Publisher: Springer
Total Pages: 248
Release: 2018-10-11
Genre: Medical
ISBN: 303002816X

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This volume summarizes recent advances in understanding the mechanisms of HIV-1 latency, in characterizing residual viral reservoirs, and in developing targeted interventions to reduce HIV-1 persistence during antiretroviral therapy. Specific chapters address the molecular mechanisms that govern and regulate HIV-1 transcription and latency; assays and technical approaches to quantify viral reservoirs in humans and animal models; the complex interchange between viral reservoirs and the host immune system; computational strategies to model viral reservoir dynamics; and the development of therapeutic approaches that target viral reservoir cells. With contributions from an interdisciplinary group of investigators that cover a broad spectrum of subjects, from molecular virology to proof-of-principle clinical trials, this book is a valuable resource for basic scientists, translational investigators, infectious-disease physicians, individuals living with HIV/AIDS and the general public.


Immunopathogenesis of HIV Infection

Immunopathogenesis of HIV Infection
Author: Anthony S. Fauci
Publisher: Springer Science & Business Media
Total Pages: 159
Release: 2012-12-06
Genre: Medical
ISBN: 3642608671

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During the last 5 years, major advances have been made in our understanding of the pathogenesis of human immunodeficiency virus (HIV) disease and in the development of new potent antiviral agents. With regard to HIV pathogenesis, several recent observations have not only changed our perspectives of HIV disease, but have been critical for the design of therapeutic strategies.


HIV-1 Integrase

HIV-1 Integrase
Author: Nouri Neamati
Publisher: John Wiley & Sons
Total Pages: 710
Release: 2011-08-10
Genre: Science
ISBN: 1118015363

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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.


Nijkamp and Parnham's Principles of Immunopharmacology

Nijkamp and Parnham's Principles of Immunopharmacology
Author: Michael J. Parnham
Publisher: Springer Nature
Total Pages: 888
Release: 2019-12-10
Genre: Medical
ISBN: 3030108112

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Principles of Immunopharmacology provides a unique source of essential knowledge on the immune response, its diagnosis and its modification by drugs and chemicals. The 4th edition of this internationally recognized textbook has been revised to include recent developments, but continues the established format, dealing with four related fields in a single volume, thus obviating the need to refer to several different textbooks. The first section of the book, providing a basic introduction to immunology and its relevance for human disease, has been updated to accommodate new immunological concepts, particularly the role of epigenetics and the latest understanding of cancer immunology. The second section on immunodiagnostics offers a topical description of widely used molecular techniques and a new chapter on imaging techniques. This is followed by a systematic coverage of drugs affecting the immune system, including natural products. This third section contains 15 updated chapters, covering classical immunopharmacological topics such as anti-asthmatic, anti-rheumatic and immunosuppressive drugs, but also deals with antibiotics, plant-derived and dietary agents, with new chapters on monoclonal antibodies, immunotherapy in sepsis and infection, drugs for soft-tissue autoimmunity and cell therapy. The book concludes with a chapter on immunotoxicology and drug safety tests. Aids to the reader include a two-column format, glossaries of technical terms and appendix reference tables. The emphasis on illustrations is maintained from the first three editions. The book is a valuable single reference for undergraduate and graduate medical and biomedical students, postgraduate chemistry and pharmacy students, researchers in chemistry, biochemistry and the pharmaceutical industry and researchers lacking basic immunological knowledge, who want to understand the actions of drugs on the immune system.


Antiviral RNAi

Antiviral RNAi
Author: Ronald P. van Rij
Publisher: Humana Press
Total Pages: 0
Release: 2011-03-08
Genre: Medical
ISBN: 9781617790362

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Viruses and RNAi share an intricate relationship at many levels. RNAi is an important antiviral defense mechanism in plants and invertebrates, microRNAs – of viral or cellular origin – affect many aspects of virus biology, and replication of many, if not all, mammalian viruses can be suppressed by RNAi. Antiviral RNAi: Concepts, Methods, and Applications provides a collection of protocols for the analysis of viral small RNAs and natural antiviral RNAi responses as well as for the development and optimization of RNAi-based antiviral drugs. As RNAi is a central regulatory mechanism in the cell, the methods in this volume can also be applied out of the context of a virus infection. Divided into five convenient parts, this detailed volume reviews important basic concepts in the field of antiviral RNAi, provides experimental and bio-informatic tools for the analysis of small silencing RNAs, covers methods to biochemically dissect RNAi-based antiviral defense and viral counter-defense mechanisms, describes methods for the design, expression, and delivery of therapeutic antiviral siRNAs, and finally presents genome-wide RNAi approaches for the identification of factors involved in virus replication. Written in the highly successful Methods in Molecular BiologyTM series format, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and accessible, Antiviral RNAi: Concepts, Methods, and Applications serves as an ideal guide for both novice and experienced researchers alike striving to dissect the role of RNAi in the viral life cycle or to further boost the development of novel therapeutics and experimental tools based on RNAi technology.