Download or read book The Structural Dynamics of Human Immunodeficiency Virus Type I Reverse Transcriptase written by James Malcolm Seckler and published by . This book was released on 2011 with total page 168 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human Immunodeficiency Virus Type 1 Reverse Transcriptase (RT) is the protein in HIV responsible for transcribing viral RNA into double stranded DNA, making it an essential component in viral infectivity and the most popular target for anti-viral therapies for HIV. Over the years, a plethora of inhibitors for RT have been developed, and many of them are currently approved for clinical use. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) are small molecules that act as non-competitive, allosteric inhibitors of RT, binding in a binding pocket inside of the polymerase domain of RT and hampering enzymatic activity. Although this is a widely used class of viral inhibitor, the mechanism of inhibition is currently unknown. In addition to this, most current knowledge of RT is concentrated on the heterodimer, while little is known of the monomeric precursors to this structure. In this study we employ HXMS and SAXS to probe the solution structural dynamics and solution structure of RT heterodimer and monomers. We show that the p51 subunit does not form the stable core of the protein. Rather the core consists of the fingers and palm subdomains of both subunits. A ß-sheet that forms half of the NNRTI binding site undergoes slow cooperative unfolding, which is slowed by several orders of magnitude upon NNRTI binding. In addition to this, HXMS analysis reveals an allosteric network of regions that spans both subunits of the RT heterodimer. This network is thought to play a vital role in RT inhibition. The structural dynamics and solution structure of RT monomers were determined, revealing that the monomers were structured but more flexible in solution compared to the solution structure of the heterodimer. HXMS revealed that the monomers had nearly identical secondary structure, with the main difference being slow cooperative unfolding in the p66 thumb subdomain. SAXS revealed that both monomers exist in an ensemble of conformation. The polymerase domain of both monomers exists both in an open p66-like conformation, a closed p51-like conformation, and several unique conformations. This research lays the foundation for a novel method of drug screening and discovery.
Download or read book Human Immunodeficiency Virus Reverse Transcriptase written by Stuart LeGrice and published by Springer Science & Business Media. This book was released on 2013-07-23 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Reverse Transcriptase (RT) of Human Immunodeficiency Virus Type 1 (HIV-1) arguably ranks amongst one of the most extensively studied retroviral enzymes. Heterologous expression and purification of HIV-1 RT in the early eighties, approval of the first nucleoside analogue RT inhibitor (NRTI) in 1987, discovery of resistance to RT inhibitors, approval of the first non-nucleoside analogue RT inhibitor (NNRTI) in 1996 and the various crystal structures of RT with and without bound substrate(s) and/or inhibitors represent only a few of the important milestones that describe the a bench-to-bedside success in the continuing effort to combat HIV-1 infection and its consequences. Nucleoside and nonnucleoside RT inhibitors remain important components in frequently used drug regimens to treat the infection. RT inhibitors also play important roles in recently validated strategies to prevent transmission of the virus. The relevance of HIV-1 RT as a drug target has simultaneously triggered interest in basic research studies aimed at providing a more detailed understanding of interactions between proteins, nucleic acids, and small molecule ligands in general terms. In light of the ever-growing knowledge on structure and function of HIV-1 RT, this enzyme serves as a valuable “model system” in efforts to develop novel experimental tools and to explain biochemical processes. This monograph is designed to provide an overview of important aspects in past and current HIV-1 RT research, with focus on mechanistic aspects and translation of knowledge into drug discovery and development. The first section includes chapters with emphasis placed on the coordination of the RT-associated DNA polymerase and ribonuclease H (RNase H) activities. The second covers mechanisms of action and future perspectives associated with NRTIs and NNRTIs, while the third section includes chapters focusing on novel strategies to target the RT enzyme. Chapters of the final part are intended to discuss mechanisms involved in HIV variability and the development of drug resistance. We hope that these contributions will stimulate interest, and encourage research aimed at the development of novel RT inhibitors. The lack of bona fide RNase H inhibitors with potent antiviral activity provides an example for challenges and opportunities in the field.
Download or read book Structural Analysis of the Catalytic Region of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase written by Jason Derek Merker and published by . This book was released on 1996 with total page 62 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Structure function Studies on the Human Immunodeficiency Virus Type 1 Reverse Transcriptase written by Michael Rostam Bavand and published by . This book was released on 1993 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Virus Dynamics Mathematical Principles of Immunology and Virology written by Martin Nowak and published by Oxford University Press, UK. This book was released on 2000-11-23 with total page 253 pages. Available in PDF, EPUB and Kindle. Book excerpt: This groundbreaking book describes the emerging field of theoretical immunology, in particular the use of mathematical models to describe the spread of infectious diseases within patients. It reveals fascinating insights into the dynamics of viral and other infections, and the interactions between infectious agents and immune responses. Structured around the examples of HIV/AIDS and hepatitis B, Nowak and May show how mathematical models can help researchers to understand the detailed dynamics of infection and the effects of antiviral therapy. Models are developed to describe the dynamics of drug resistance, immune responses, viral evolution and mutation, and to optimise the design of therapy and vaccines. - ;We know, down to the tiniest details, the molecular structure of the human immunodeficiency virus (HIV). Yet despite this tremendous accomplishment, and despite other remarkable advances in our understanding of individual viruses and cells of the immune system, we still have no agreed understanding of the ultimate course and variability of the pathogenesis of AIDS. Gaps in our understanding like these impede our efforts towards developing effective therapies and preventive vaccines. Martin Nowak and Robert M May describe the emerging field of theoretical immunology in this accessible and well- written text. Using mathematical modelling techniques, the authors set out their ideas about how populations of viruses and populations of immune system cells may interact in various circumstances, and how infectious diseases spread within patients. They explain how this approach to understanding infectious diseases can reveal insights into the dynamics of viral and other infections, and the interactions between infectious agents and immune responses. The book is structured around the examples of HIV/AIDS and Hepatitis B virus, although the approaches described will be more widely applicable. The authors use mathematical tools to uncover the detailed dynamics of the infection and the effects of antiviral therapy. Models are developed to describe the emergence of drug resistance, and the dynamics of immune responses, viral evolution, and mutation. The practical implications of this work for optimisation of the design of therapy and vaccines are discussed. The book concludes with a glance towards the future of this fascinating, and potentially highly useful, field of study. - ;... an excellent introduction to a field that has the potential to advance substantially our understanding of the complex interplay between virus and host - Nature
Download or read book Optimisation of Drugs Against the Human Immunodeficiency Virus Type 1 HIV 1 Enzymes Reverse Transcriptase and Protease by Means of Kinetic and Structural Studies written by Kristina Bäckbro and published by . This book was released on 1997 with total page 52 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Structure function Analysis of the Ribonuclease H Domain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase written by Nick Mario Cirino and published by . This book was released on 1995 with total page 350 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Human Immunodeficiency Virus Type 1 Reverse Transcriptase written by Yvonne Kew and published by . This book was released on 1997 with total page 304 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Molecular Analysis of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase in Infectious Virus written by Alok Mohan Mulky and published by . This book was released on 2005 with total page 338 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Structure substrate Binding Relationships of HIV 1 Reverse Transcriptase written by Steve Chien-Wen Huang and published by . This book was released on 1994 with total page 184 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Biochemical Characteristics of Different Subtypes of Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Its Interactions with the Host Factor written by Seongmi Kim and published by . This book was released on 2017 with total page 87 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human immunodeficiency virus (HIV) is divided into type 1 (HIV-1) and type 2 (HIV-2). Whereas HIV-2 accounts for 5% of global infections, HIV-1 is responsible for 95% of the global pandemic. HIV-1 is classified into four groups; M, N, O and P. Group M is the most prevalent, including subtypes or clades of A-D, F-H, J, K, over 100 Circulating Recombinant Forms (CRFs), and several Unique Recombinant Forms (URFs). In developed countries (i.e. countries in North America, Western Europe, and Australia), HIV-1B is the most prevalent strain. However, it accounts for only about 12% of worldwide infections. On the other hand, HIV-1C, which is most prevalent in Low- and Middle-Income Countries (LMICs) (e.g. India, Brazil, and many countries in Sub-Saharan Africa), accounts for [approximately]52% of all HIV infections. Due to its prevalence in developed countries, HIV-1B has been the major target of HIV studies and anti-HIV drug development. However, it has been reported that HIV-1non-B patients have higher rates of treatment failure than HIV-1B patients. To understand the mechanism behind this observation, we applied in vitro biochemical assays, which were performed with four patient-derived reverse transcriptase (RT) proteins isolated from HIV-1B, HIV-1C, CRF01_AE, and CRF02_AG viruses. RT is the HIV enzyme that generates viral DNA from genomic RNA during the early stages of infection, and it is the target for many anti-HIV drugs. RT inhibitors are divided into two types depending on their structure. First, Nucleoside/nucleotide Reverse Transcriptase Inhibitors (NRTIs), which bind the active site of the RT and act as chain terminators. In addition, a new type of NRTI, called 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), works as a translocation inhibitor. Second, Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) inhibit RT by binding to an allosteric site. Nevirapine (NVP) belongs to the first generation of NNRTIs, however HIV-1 develops resistance mutations frequently during NVP treatment. Rilpivirine (RPV) has been developed to target NVP-resistant viruses but it is not frequently used in LMICs. In this study, we determined the biochemical characteristics of HIV-1 RTs from various subtypes and determined kinetic constants of inhibition by EFdA, NVP, and RPV. The results show that all of the tested HIV-1 RTs incorporate EFdA with better efficiency than their natural cognate substrate, dATP, which suggests that EFdA would be effective against all of the tested HIV-1 subtypes. Furthermore, generally NVP binds RTs with a lower affinity than RPV, implying that NVP would be a less effective inhibitor than RPV. However, in the case of CRF02_AG RT, NVP binds with similar affinity to RPV, suggesting CRF02_AG patients may respond better to NVP than patients infected with other subtypes. HIV-1C has less binding affinity to RPV than other subtypes, which is consistent with clinical reports showing that HIV-1C patients have a higher rate of treatment failure with RPV. Finally, we have studied the effect of a host factor, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), on HIV-1 RT. APOBEC3G (A3G) has been reported to inhibit several retroviral infections. To date, there are two established mechanisms of this inhibition, which are hyper-mutagenesis and roadblock. In this study, we investigated a third mechanism, the direct inhibition of HIV-1 RT, using in vitro RT assays. Our results showed that A3G does inhibit the activity of HIV-1 RT by affecting the catalytic rate of dNTP incorporation (k[subscript cat]), supporting the direct inhibition mechanism. Interestingly, A3G had similar inhibitory activity against a related viral RT (from Moloney Murine Leukemia Virus), but no activity against DNA polymerase I.
Download or read book Characterizing Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Integrase Interaction written by Shewit Tekeste and published by . This book was released on 2014 with total page 83 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human immunodeficiency virus type 1 (HIV-1) replication requires the reverse transcription of its RNA genome into double-stranded DNA copies within the cytoplasm before integration into the host chromosome. Reverse transcriptase (RT) and integrase (IN) are the viral enzymes responsible for catalyzing the essential steps of reverse transcription and integration, respectively. While numerous studies have led to a greater understanding of the functional roles that RT and IN individually play in HIV-1 replication, little is known about the functional role of RT-IN complex formation in vivo. We hypothesize that RT-IN interaction has functional significance in HIV-1 reverse transcription and replication kinetics. We have mapped the putative binding domain of RT on IN to nine residues on the IN C-terminal domain (CTD). We tested the significance of RT-IN interaction on reverse transcription and viral replication, and identified the step at which viral replication of these IN mutants become defective. We observed impairment of viral cDNA synthesis in viruses harboring IN mutations at the putative RT-binding surface, supporting our hypothesis that the RT-IN interaction during the reverse transcription step is biologically relevant. We have developed a pharmacological approach to study and screen for inhibitors against the RT-IN interaction. Lastly, we have also initiated biochemical studies to determine the IN binding domain domain on RT to contribute to the full understanding of the binding mechanism.
Download or read book HIV 1 Integrase written by Nouri Neamati and published by John Wiley & Sons. This book was released on 2011-08-10 with total page 710 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.
Download or read book Conformational Dynamics Plays a Significant Role in HIV Reverse Transcriptase Resistance and Substrate Selection written by Virginia Myanh Nguyen and published by . This book was released on 2012 with total page 66 pages. Available in PDF, EPUB and Kindle. Book excerpt: Human immunodeficiency virus reverse transcriptase (HIV RT) is a virally encoded polymerase responsible for replicating the HIV genome. Most HIV treatments include nucleotide RT inhibitors (NRTIs) which inhibit HIV RT replication by serving as a substrate for the polymerase reaction but then blocks subsequent polymerization after incorporation. However, resistance to these NRTIs may occur through specific mutations in HIV RT that increase the discrimination of HIV RT for natural nucleotides over NRTIs. The role of enzyme conformational dynamics in specificity and substrate selection was studied using transient kinetic methods on HIV RT enzymes that have been site-specifically labeled with a conformationally sensitive fluorophore, to measure the rates of binding and catalysis. First, HIV RT with the mutation of lysine to arginine at the residue position 65 (K65R) was examined for its resistance against the NRTI tenofovir diphosphate (TFV), an acyclic deoxyadenosine triphosphate (dATP) analog. It was found that HIV RT K65R resistance to TFV was achieved through decreased rates of catalysis and increased rates of dissociation for TFV over dATP when compared with the kinetics of wild-type HIV RT. Moreover, global fitting analysis confirmed a mechanism where a large conformational change, after initial ground state binding of the substrate, contributed significantly to enzyme specificity. This led to our investigation of the molecular basis for enzyme specificity using HIV RT as a model system. Again, transient kinetic methods were applied with the addition of molecular dynamics simulations. The simulated results were substantiated by the corroborating experimental results. It was found that a substrate-induced conformational change in the transition of HIV RT from an open nucleotide-bound state to a closed nucleotide-bound state was the major determinant in enzyme specificity. The molecular basis for substrate selection resulted from the molecular alignments of the substrate in the active-site, which induced the conformational change. When the correct nucleotide was bound, optimal molecular interactions in the active-site yielded a stably closed complex, which promoted nucleotide incorporation. In contrast, when an incorrect nucleotide was bound, the molecular interactions at the active-site were not ideal, which yielded an unstable closed complex, which promoted substrate dissociation rather than incorporation.
Download or read book Mandell Douglas and Bennett s Principles and Practice of Infectious Diseases E Book written by John E. Bennett and published by Elsevier Health Sciences. This book was released on 2019-08-08 with total page 5208 pages. Available in PDF, EPUB and Kindle. Book excerpt: For four decades, physicians and other healthcare providers have trusted Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases to provide expert guidance on the diagnosis and treatment of these complex disorders. The 9th Edition continues the tradition of excellence with newly expanded chapters, increased global coverage, and regular updates to keep you at the forefront of this vitally important field. Meticulously updated by Drs. John E. Bennett, Raphael Dolin, and Martin J. Blaser, this comprehensive, two-volume masterwork puts the latest information on challenging infectious diseases at your fingertips. Provides more in-depth coverage of epidemiology, etiology, pathology, microbiology, immunology, and treatment of infectious agents than any other infectious disease resource. Features an increased focus on antibiotic stewardship; new antivirals for influenza, cytomegalovirus, hepatitis C, hepatitis B., and immunizations; and new recommendations for vaccination against infection with pneumococci, papillomaviruses, hepatitis A, and pertussis. Covers newly recognized enteroviruses causing paralysis (E-A71, E-D68); emerging viral infections such as Ebola, Zika, Marburg, SARS, and MERS; and important updates on prevention and treatment of C. difficile infection, including new tests that diagnose or falsely over-diagnose infectious diseases. Offers fully revised content on bacterial pathogenesis, antibiotic use and toxicity, the human microbiome and its effects on health and disease, immunological mechanisms and immunodeficiency, and probiotics and alternative approaches to treatment of infectious diseases. Discusses up-to-date topics such as use of the new PCR panels for diagnosis of meningitis, diarrhea and pneumonia; current management of infected orthopedic implant infections; newly recognized infections transmitted by black-legged ticks in the USA: Borrelia miyamotoi and Powassan virus; infectious complications of new drugs for cancer; new drugs for resistant bacteria and mycobacteria; new guidelines for diagnosis and therapy of HIV infections; and new vaccines against herpes zoster, influenza, meningococci. PPID continues its tradition of including leading experts from a truly global community, including authors from Australia, Canada and countries in Europe, Asia, and South America. Features more than 1,500 high-quality, full-color photographs—with hundreds new to this edition.
Download or read book Mandell Douglas and Bennett s Principles and Practice of Infectious Diseases E Book written by John E. Bennett and published by Elsevier Health Sciences. This book was released on 2014-09-02 with total page 5094 pages. Available in PDF, EPUB and Kindle. Book excerpt: After thirty five years, Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition is still the reference of choice for comprehensive, global guidance on diagnosing and treating the most challenging infectious diseases. Drs. John E. Bennett and Raphael Dolin along with new editorial team member Dr. Martin Blaser have meticulously updated this latest edition to save you time and to ensure you have the latest clinical and scientific knowledge at your fingertips. With new chapters, expanded and updated coverage, increased worldwide perspectives, and many new contributors, Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th Edition helps you identify and treat whatever infectious disease you see. Get the answers to any questions you have with more in-depth coverage of epidemiology, etiology, pathology, microbiology, immunology, and treatment of infectious agents than you’ll find in any other ID resource. Apply the latest knowledge with updated diagnoses and treatments for currently recognized and newly emerging infectious diseases, such as those caused by avian and swine influenza viruses. Put the latest knowledge to work in your practice with new or completely revised chapters on Influenza (new pandemic strains); New Middle East Respiratory Syndrome (MERS) Virus; Probiotics; Antibiotics for resistant bacteria; Antifungal drugs; New Antivirals for hepatitis B and C; Clostridium difficile treatment; Sepsis; Advances in HIV prevention and treatment; Viral gastroenteritis; Lyme Disease; Helicobacter pylori; Malaria; Infections in immunocompromised hosts; Immunization (new vaccines and new recommendations); and Microbiome. Benefit from fresh perspectives and expanded global insights from an expanded team of American and International contributors. Martin Blaser, MD, a leading expert and Muriel G. and George W. Singer Professional of Translational Medicine at New York University School of Medicine, joins veteran PPID editors John E. Bennett, MD, and Raphael Dolin, MD to continue a legacy of excellence. Find and grasp the information you need easily and rapidly with newly added chapter summaries.
Download or read book Nucleic Acid Polymerases written by Katsuhiko S. Murakami and published by Springer Science & Business Media. This book was released on 2013-10-22 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a review of the multitude of nucleic acid polymerases, including DNA and RNA polymerases from Archea, Bacteria and Eukaryota, mitochondrial and viral polymerases, and other specialized polymerases such as telomerase, template-independent terminal nucleotidyl transferase and RNA self-replication ribozyme. Although many books cover several different types of polymerases, no book so far has attempted to catalog all nucleic acid polymerases. The goal of this book is to be the top reference work for postgraduate students, postdocs, and principle investigators who study polymerases of all varieties. In other words, this book is for polymerase fans by polymerase fans. Nucleic acid polymerases play a fundamental role in genome replication, maintenance, gene expression and regulation. Throughout evolution these enzymes have been pivotal in transforming life towards RNA self-replicating systems as well as into more stable DNA genomes. These enzymes are generally extremely efficient and accurate in RNA transcription and DNA replication and share common kinetic and structural features. How catalysis can be so amazingly fast without loss of specificity is a question that has intrigued researchers for over 60 years. Certain specialized polymerases that play a critical role in cellular metabolism are used for diverse biotechnological applications and are therefore an essential tool for research.
