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Author: Guido Silvestri Publisher: Springer ISBN: 303002816X Category : Medical Languages : en Pages : 248
Book Description
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.
Author: Guido Silvestri Publisher: Springer ISBN: 303002816X Category : Medical Languages : en Pages : 248
Book Description
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.
Author: Guido Silvestri (Professor of pathology and laboratory medicine) Publisher: ISBN: 9783030028176 Category : HEALTH & FITNESS Languages : en Pages :
Book Description
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.
Author: Guido Poli Publisher: ISBN: 9781071618714 Category : Electronic books Languages : en Pages : 451
Book Description
This book details the development of methods and models to study the HIV-1 viral reservoir with the ultimate goal of achieving a functional cure of HIV infection. Chapters are divided into six parts covering cell lines, in vitro and ex vivo primary cell models of persistent infection, in vitro and ex vivo tissue-derived models, infected animal models human immune cells, methods of detection and analysis of the reservoir, and current approaches to achieve either a functional cure or cART-free long-term remission. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and reagents, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, HIV Reservoirs: Methods and Protocols provides a comprehensive, updated collection of state-of-art methodologies and models to tackle the HIV-1 viral reservoir.
Author: Linqi Zhang Publisher: Springer ISBN: 981130484X Category : Medical Languages : en Pages : 318
Book Description
This book provides a comprehensive review of the major barriers to HIV cure and vaccine. It covers the fundamental virology and immunology leading to HIV transmission, protection from infection and long term HIV persistence on antiretroviral therapy. In addition, strategies being tested to eliminate persistent HIV and the rational design of vaccines to induce protective immunity are covered. This book also discusses the challenges related to the design of clinical trials for testing the safety and efficacy of these innovative approaches. This book will provide a systematic overview and also discuss controversial issues for researchers in virology and immunology, as well as practicing physicians, and scientists in the pharmaceutical industry.
Author: Paula Campos Soto Publisher: ISBN: Category : Languages : en Pages : 85
Book Description
Highly active antiretroviral therapy (HAART) in individuals infected with HIV-1 often lowers plasma viremia to below detection limits. However, cessation of therapy in such individuals results in rebound of virus replication, indicating that HIV-infected cells persist. Resting, memory CD4 T cells in the blood and lymph nodes comprise the major reservoir for persistent HIV infection. To devise new efficient strategies targeted toward the eradication of the latently infected HIV reservoir, a better understanding of the molecular and cellular basis for viral latency is needed. Dr. Spina's research group has developed a unique in vitro T cell model to study HIV latency. In my thesis project, I have used and modified this cell model to investigate: 1) the cellular proliferation and activation requirements for the development of latently infected CD4 cells, and 2) the transcriptional activity of the HIV provirus in a nonproductive, persistent infection. Results from the first research phase demonstrated that HIV infection immediately prior to T cell stimulation resulted in production of the greatest number of latently infected cells. Infected cells that did not divide, or divided only a few times, following stimulation went on to form the latently infected cell pool. The vast majority of acutely infected, activated CD4 cells were not able to survive multiple rounds of cell division in combination with the cytopathic effects of HIV. Rather, the subset of CD4 cells that exhibited minimal activation, in the presence of fully-activated and productively infected T cells, survived with latent HIV infection. In the second phase of research, a sensitive qRT-PCR assay was used to examine the transcriptional activity of the HIV provirus in resting, infected CD4 cells. Multiple different species of HIV mRNA were found, with unspliced gag transcripts being the most abundant followed by singly-spliced env, total multiply-spliced, nef, and tat species. Detection of viral RNA transcription in latently infected T cells from our in vitro model has raised the possibility that HIV latency is not maintained by a simple passive mechanism, but may involve active interactions between viral products and cell processes that influence viral latency and reactivation.
Author: Michel Neidhart Publisher: Academic Press ISBN: 0127999205 Category : Science Languages : en Pages : 546
Book Description
DNA Methylation and Complex Human Disease reviews the possibilities of methyl-group-based epigenetic biomarkers of major diseases, tailored epigenetic therapies, and the future uses of high-throughput methylome technologies. This volume includes many pertinent advances in disease-bearing research, including obesity, type II diabetes, schizophrenia, and autoimmunity. DNA methylation is also discussed as a plasma and serum test for non-invasive screening, diagnostic and prognostic tests, as compared to biopsy-driven gene expression analysis, factors which have led to the use of DNA methylation as a potential tool for determining cancer risk, and diagnosis between benign and malignant disease. Therapies are at the heart of this volume and the possibilities of DNA demethylation. In cancer, unlike genetic mutations, DNA methylation and histone modifications are reversible and thus have shown great potential in the race for effective treatments. In addition, the authors present the importance of high-throughput methylome analysis, not only in cancer, but also in non-neoplastic diseases such as rheumatoid arthritis. Discusses breaking biomarker research in major disease families of current health concern and research interest, including obesity, type II diabetes, schizophrenia, and autoimmunity Summarizes advances not only relevant to cancer, but also in non-neoplastic disease, currently an emerging field Describes wholly new concepts, including the linking of metabolic pathways with epigenetics Provides translational researchers with the knowledge of both basic research and clinic applications of DNA methylation in human diseases
Author: Anthony S. Fauci Publisher: Springer Science & Business Media ISBN: 3642608671 Category : Medical Languages : en Pages : 159
Book Description
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.
Author: Thomas E. Shenk Publisher: Springer Science & Business Media ISBN: 3540773495 Category : Medical Languages : en Pages : 477
Book Description
This volume has gathered some of the experts in the field to review aspects of our understanding of CMV and to offer perspectives of the current problems associated with CMV. The editors and authors hope that the chapters will lead to a better understanding of the virus that will assist in the development of new and unique antivirals, a protective vaccine, and a full understanding of CMV's involvement in human disease.
Author: Siddharth Subhas Dey Publisher: ISBN: Category : Languages : en Pages : 344
Book Description
With 33.3 million people presently infected with Human Immunodeficiency Virus-1 (HIV-1), combined with the 2.6 million new infections and 1.8 million AIDS related death in 2009 alone, HIV-1 continues to be one of the biggest global pandemics and medical challenges of the new millennium. Although the development of antiretroviral drugs was a major advance in the treatment of patients infected with HIV-1, complete eradication of HIV-1 has not been possible due to two major obstacles. First, the high mutation rate of the virus coupled with its rapid replication rate has given rise to drug resistant strains of HIV-1. Furthermore, latent viral reservoirs that are not directly targeted by anti-viral therapies or by the immune system can reactivate at a later time preventing complete viral clearance from a patient. Compounding these difficulties is the global diversification of viral strains or subtypes that have widely differing sequences, resulting in unique gene regulation and pathogenesis. Following integration into the host genome, activation of viral gene expression results in the production of new progeny whereas the inability to activate gene expression could initiate the establishment of viral latency. Thus, a better understanding of the mechanisms and factors that regulate viral transcription is critical towards eliminating latent viral populations. Therefore, the focus of this work has been to investigate the role of both cellular and viral factors in regulating HIV-1 gene expression and latency using a combination of computational and experimental techniques. This work may help develop novel therapy targets and better treatment regimens for different HIV-1 subtypes while concurrently providing new insights on mammalian gene regulation. In studying viral factors that regulate gene expression in HIV-1, we focused attention on the HIV-1 promoter, a viral protein called Tat and a RNA hairpin called TAR. The error prone nature of HIV-1 replication has resulted in highly diverse viral sequences, and it is not clear how Tat, which plays a critical role in viral gene expression and replication, retains its complex functions. Although several important amino acid positions in Tat are conserved, we hypothesized that it may also harbor functionally important residues that may not be individually conserved yet appear as correlated pairs, and knowledge of such evolutionary information could help elucidate underlying mechanisms of Tat function. Using Information theory based approaches such as Mutual Information and protein engineering approaches, we found a pair of sites in Tat that are strongly coevolving and that provided insight into Tat-mediated viral transcription. In contrast to most coevolving protein residues that contribute to the same function, these studies showed that these two residues contribute to two mechanistically distinct steps in gene expression: binding the cellular protein, positive transcription-elongation factor b (P-TEFb) and promoting P-TEFb phosphorylation of the C-terminal domain in RNA Polymerase II (RNAPII). Moreover, Tat variants that mimic HIV-1 subtype B or C at these sites have evolved orthogonal strengths of P-TEFb binding vs. RNAPII phosphorylation, suggesting that subtypes have evolved alternate transcriptional strategies that could differentially impact latency while achieving similar gene expression levels. Interaction between Tat and the viral hairpin TAR is critical for efficient gene expression from the viral promoter and we therefore hypothesized that sequence diversity within these elements may dramatically alter the gene expression and latency properties of different subtype viruses. We found large differences in gene expression between subtypes using a variety of experimental models and showed that subtype TARs and Tats act independently to set the level of gene expression from the viral promoter. Further, using Mutual information and site-directed mutagenesis we showed that nucleotides in TAR are not coevolving with residues in Tat implying that HIV-1 has evolved a highly robust mechanism of activating gene expression in the face of rapid viral evolution. Similarly, the promoters of different HIV-1 subtypes have evolved different architectures of transcription factor binding sites (TFBS) that result in widely varying levels of gene expression and viral replication. Within this large diversity of TFBS in the HIV-1 promoter, we used in vitro models of HIV-1 latency to identify the minimal set of TFBS that contribute to most of the observed differences in gene expression and latency at steady state. In contract, we found that the dynamics of gene expression is dependent on both the minimal set of TFBS and other sites in the viral promoter. Identifying other targets within the viral promoter will provide better mechanistic understanding of the establishment and reactivation of HIV-1 latency as well as potentially identify new molecular targets to counter latency. While diversity in viral factors can contribute to differential regulation of viral gene expression, host factors can also play a significant role in this regulation. Since HIV-1 integrates semi-randomly within the human genome, another aspect of my thesis included studying the role of the cellular genomic location in regulating viral gene expression. We exploited the semi-random integration of HIV-1 to quantitatively study both how latent proviruses can be reactivated from different chromatin environments and to address a fundamental question in eukaryotic gene expression related to how the placement of a gene in the genome impacts its responsiveness to an input transcription factor signal. Using a tunable overexpression system for the transcription factor NF-[kappa]B RelA, we quantified HIV-1 expression as a function of RelA levels and chromatin features at a panel of viral integration sites. We demonstrated that chromatin environments at different genomic loci decouple transcription factor mediated gene expression induction thresholds from subsequent gene activation. We developed a functional relationship between gene expression, RelA levels, and chromatin accessibility that accurately predicted synergistic HIV-1 activation in response to combinatorial pharmacological perturbations. Thus, this quantitative study should help inform strategies for combinatorial therapies to combat latent HIV-1 and help unravel biological principles underlying selective gene expression in response to transcription factor inputs. Finally, after HIV-1 integrates into the host genome, it can either activate gene expression that leads to viral replication or become transcriptionally silent that can result in viral latency. Since stochastic fluctuations in HIV-1 gene expression are one of several factors that have been implicated in influencing this decision and thus in the establishment of viral latency, we investigated the role of the local chromatin environment in regulating gene expression noise. We showed that for clones with similar mean gene expression levels, those integrated into more heterochromatic regions are associated with wider mRNA and protein distributions. Using a two-state stochastic model of gene expression, we showed that the repressed chromatin gives rise to noisier gene expression by lowering the burst frequency. In addition to more clearly defining the role of the chromatin environment in regulating the establishment of viral latency, this study has implications for the role of chromatin in modulating transcriptional noise in eukaryotes and its evolutionary consequences in the placement of genes within the genome. Thus these studies of the role of sequence variation within the viral genome and its chromosomal integration site in regulating gene expression has resulted in better understanding of the mechanisms of gene expression and establishment of latency in HIV-1, while also helping to discern the role of chromatin in regulating mammalian gene expression.
Author: Guido Silvestri
Author: Guido Silvestri
Author: Guido Silvestri (Professor of pathology and laboratory medicine)
Author: Guido Poli
Author: David Gregory Brooks
Author: Linqi Zhang
Author: Paula Campos Soto
Author: Michel Neidhart
Author: Anthony S. Fauci
Author: Thomas E. Shenk
Author: Siddharth Subhas Dey