The Effect of Chronic HIV-1 Infection on Circulating B Cells and Peripheral T Follicular Helper Cells PDF Download
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Author: Katherine Joy Nicholas
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 138
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Book Description
Author: Katherine Joy Nicholas
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 138
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Book Description
Author: Francesca Chiodi
Publisher: Frontiers Media SA
ISBN: 2889454614
Category : B cells
Languages : en
Pages : 171
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Book Description
Multiple dysfunctions take place in the B cell compartment during HIV-1 infection, comprising depletion of resting memory B cells carrying serological memory to vaccines and previously met pathogens. In addition, population of B cells characterized by the expression of exhaustion markers are enlarged during HIV-1 infection. Antibodies with the capacity to neutralize a broad range of HIV-1 isolates can be detected only in a minority of infected patients, after a year or more from acute infection. An open question is whether the inability of producing neutralizing HIV-1 antibodies is somehow linked to the B cell immunopathology observed in patients. In this research topic we invited scientists to summarize the current state of knowledge on regulation and development of B cells and antibody responses during HIV-1 infection; fifteen contributions were received comprising both reviews and original articles. The articles are related to B cell dysfunctions identified in HIV-1 infected individuals, production of different types of antibodies (neutralizing versus non neutralizing, and of different isotypes) in vivo during HIV-1 infection and the biological factors which may impact on this process, clinical potential and applications of anti-HIV antibodies and how to achieve neutralizing antibody responses to HIV-1 epitopes upon vaccination. The topic has gathered articles on front-line research undertaken in the field of B cells and antibodies in HIV-1 infection. It is our hope that the collection of articles presented in this book may be useful for new and experienced scholars in the field and add a piece to the complex puzzle of knowledge needed for the development of an HIV-1 vaccine.
Author: Bradley Salvatore
Publisher:
ISBN:
Category :
Languages : en
Pages : 54
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Book Description
The role and function of human T follicular regulatory (TFR) cells in healthy individuals are not completely understood, partly due to its previous grouping with T follicular helper (TFH) cells and partly due to the difficulty in obtaining human secondary lymphoid tissues. A majority of the studies of these two T cell subsets have been done in mice. Up to date, there are only a few studies of human TFR cells in HIV infection in the lymph nodes and the spleen, and peripheral blood TFR cells have not been well defined. The understanding of TFR cells and its phenotypic difference from TFH cells are crucial in the understanding of the humoral response against HIV and other diseases. Also, elucidating TFR cells' contribution to HIV persistence is important in the path of finding a functional cure for HIV infection. In this Master Thesis, I have examined TFH and TFR cells and their surface markers in human peripheral blood. In Chapter 2 ("Characterization of T Follicular Helper Cells and T Follicular Regulatory Cells in HIV-Infected and non-Infected Individuals"), I investigated the phenotypic characteristics of peripheral blood TFH (pTFR) and TFH (pTFH) cells in peripheral blood mononuclear cells (PBMC) of HIV-infected and HIV non-infected individuals from the Multicenter AIDS Cohort Study (MACS). pTFR cells uniquely expressed the natural T regulatory canonical marker, forkhead box P3 (FOXP3), while pTFH uniquely expressed the TFH cells' master regulatory, B cell lymphoma 6 (BCL6). An effective way to identify pTFH and pTFR in PBMC only using their surface markers would allow for further functional studies. Collectively, this thesis should further advance the field of basic research of T cells and the field of HIV reservoir, bringing the field closer to a functional cure of HIV Infection.
Author: Guido Silvestri
Publisher: Springer
ISBN: 303002816X
Category : Medical
Languages : en
Pages : 253
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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: Christian Raul Aguilera-Sandoval
Publisher:
ISBN:
Category :
Languages : en
Pages : 199
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Book Description
Although it is well-documented that T cells are crucial in the pathogenesis of human immunodeficiency virus type 1 (HIV-1) yet the dynamic interplay between HIV-1 and T cells has not been fully elucidated. The effects that HIV-1 has on T cell diversity and the effects that T cell diversity has on HIV viral escape have not been well characterized; an understanding of these effects could have crucial implications for design of CTL vaccines. In particular, such information could provide insights needed to develop methods for reconstitution of sufficient diversity in the immune systems of HIV+ persons to allow CTL vaccines to be effective. Furthermore, such information could be helpful in the development of CTL vaccines against semi-conserved epitopes, so as to prevent viral escape. These are the aims this dissertation will attempt to address. One major problem with the current approach to HIV-1 vaccine development is that the strategies currently being employed ultimately fail; this is mostly, but not entirely, due to HIV-1's high rate of mutation. This ultimately results in the escape of the virus from vaccine-induced immunity, thereby rendering such vaccines useless. Both CD4+ and CD8+ T cells play a major role in immune responses to HIV-1. However, during the course of infection, CD4+ T cells are depleted, not only in number, but also in diversity. Limited CD4+ T cell diversity cripples the immune system, as such CD4+ T cells are not able to provide the help necessary for effective innate and adaptive immune system responses to HIV, including help to CTL, which is of particular importance for this dissertation. CTL responses constitute one of the crucial arms of the immune system that is highly responsible for responding to HIV-1 infection. However, immune defenses mediated by CTL ultimately fail in HIV infection, which is, again, also largely (but not entirely) due to high rates of HIV-1 mutation that cause constant viral escape, which, in turn, drives chronic immune activation and ultimately CTL exhaustion. We have addressed each of these problems in this dissertation. In Chapter Two, we present results of studies in which we examined thymic output and CD4+ T cell diversity from HIV+ persons who were perinatally infected, were in treatment and had lived with the infection for over two decades. In Chapter Three, we present results of studies in which we screened for CTL responses against the gag 162-173 KAFSPEVIPMF epitope from multiple persons and identified and cloned the TCR responsible for these responses, using a novel technique TCR identification and cloning technique that we also present in this chapter. Finally, we functionally tested the cloned KF11-specific TCR to confirm that this panel was able to recognize and lyse the most common circulating variants of the KF11 epitope. The results presented in Chapter Two of this dissertation show that HIV+ participants had reduced CD4+ T cell levels, with predominant depletion of the memory subset, but preservation of naive cells. In most of these HIV+ participants, levels of CD4+ T cells that were recent thymic emigrants' CD4+ T cell levels were normal, and enhanced thymopoiesis was present, as indicated by higher proportions of CD4+ T cells containing TCR recombination excision circles. Memory CD4+ T cell depletion was highly associated with CD8+ T-cell activation in HIV-1- infected persons, and plasma interlekin-7 levels were correlated with levels of naive CD4+ T cells, suggesting activation-driven loss and compensatory enhancement of thymopoiesis. Deep sequencing of CD4+ T cell receptor sequences in HIV+ subjects who had high levels of compensatory enhancement of thymopoiesis revealed supranormal TCR diversity, providing additional evidence of enhanced thymic output. In Chapter Three we introduce and describe an inexpensive new technique to quickly and efficiently identify, clone and functionally test epitope-specific TCR. Using this new technique and samples from multiple HIV+ HLA-B*5701 persons, we identified, cloned and functionally tested four KF11-specific TCR. The four identified KF11-specific TCR were able to recognize and lyse target cells that were peptide-loaded with the six most common circulating variants of KF11. These six variants make up 97% of all circulating variants, according to the Los Alamos HIV database. The functional avidity and killing efficiency of the KF11-specific TCR were also investigated. Consonant with prior supporting data on KF11-specific TCR, the functional avidity observed for these four KF11-specific TCR had a range of 89 ng/ml to 832 ng/ml. One of the KF11-specific TCR was tested for its ability to lyse HIV-infected cells. This TCR was able to lyse cells infected with three of the four variants that were previously recognized and lysed in the peptide-loaded target cells. If these TCR are validated in vivo, and they are to prevent viral escape, the process could be repeated with other HLA restricted epitopes in order to develop a new treatment against HIV-1.
Author: R. Ahmed
Publisher: Wiley-Blackwell
ISBN:
Category : Medical
Languages : en
Pages : 754
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Book Description
Persistent Viral Infections Edited by Rafi Ahmed Emory Vaccine Center, Atlanta, USA and Irvin S. Y. Chen UCLA School of Medicine, Los Angeles, USA During the past decade much of our attention has focused on diseases associated with viral persistence. Major breakthroughs in immunology, and the advent of molecular approaches to study pathogenesis have increased our understanding of the complex virus-host interactions that occur during viral persistence. Persistent Viral Infections focuses on: * The pathogenesis and immunology of chronic infections * Animal models that provide, or have the potential to provide, major insights This volume will be essential reading for virologists, immunologists, oncologists and neurologists.
Author: Mariana Guedes Weber
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Human immunodeficiency virus-1 (HIV) epidemic continues to pose a major infectious disease threat to human health, affecting 38 million people worldwide. Additionally, about two million new HIV infections are diagnosed each year. The combination antiretroviral therapy (ART) is effective in suppressing HIV replication and reducing morbidity and mortality. However, ART is unable to eradicate the latent HIV reservoirs and does not consistently translate into complete immune recovery. Novel combination approaches are needed to prevent new infections along with therapies that are able to enhance and empower the host immune system for achieving full recovery in HIV infected individuals. HIV infection is characterized by CD4+ T cell loss, chronic immune activation and impaired host immune functions. A better understanding of the factors that induce immune modulation and enhance anti-viral immunity is important in developing innovative therapeutic or prevention strategies for HIV infection. In this dissertation project, we investigated cellular and viral factors that impact anti-HIV immunity by using the preclinical non-human primate model of AIDS. Two independent approaches were applied to investigate the impact of immune modulation on generating anti-viral immunity. In the first study (Chapter 2), the impact of mesenchymal stem cell (MSCs) therapy was investigated in enhancing anti-viral immunity and controlling chronic immune activation in chronically simian immunodeficiency virus-infected rhesus macaques. In the second study (Chapter 3), the effect of subclinical cytomegalovirus (CMV) infection on the induction of vaccine immunity in response to RhCMV/SIV and to inactivated influenza vaccine was investigated. Since immune cell subsets are an integral component of generating host immune response to vaccines and viral infections, we investigated the effect of SIV infection on the prevalence and functions of immune cells including T cell subsets and natural killer (NK) cells (Chapter 3). Chapter 2: Administration of allogenic mesenchymal stem cells to chronically SIV infected rhesus macaques resulted in enhanced levels of SIV specific antibody response and cytotoxic T cell activity. This increased anti-viral immunity was associated with partial restoration of activated B cell and T follicular helper cell subsets, enhanced mucosal lymphoid germinal center structure and increased localization and trapping of the virus in the lymphoid follicles. These changes coincide with a striking decline in viral RNA levels in peripheral blood and in gut mucosal lamina propria. The enhanced anti-viral immunity was associated with a gene signature enriched for the B and Tfh cell functions and enhanced antigen presentation. Chapter 3: There is a substantial level of variation at the population level in the immune response to anti-viral vaccines and their efficacy which is attributed to host immune status. Several factors including the presence of subclinical viral infections, age and microbiota can modulate the immune functionality. To investigate the factors that contribute to individual variation in immune response to anti-viral immunity, we assessed host immune response in rhesus macaques following immunization with two vaccines, an inactive trivalent influenza vaccine (TIV) and an SIV vaccine presented in an attenuated live CMV vector (RhCMV/SIV). Animals that generated higher vaccine immunity (anti-viral antibodies) to influenza vaccine were identified as high responders. The same animals also mounted a higher immune response to SIV vaccine. There were no marked differences in the composition of the microbiota at the genus level. However, Paraprevotelaceae was enriched in the high vaccine responder group and its prevalence positively correlated with the magnitude of antibody responses to influenza and SIV gag vaccines. The most pronounce effect on vaccine immunity correlated with the presence of subclinical CMV infection. The CMV-negative animals had higher vaccine responses compared to CMV positive animals. Thus, the presence of subclinical CMV infection and immune activation modulated immunity to anti-viral vaccines. Chapter 4: Composition and function of immune cell subsets determine host immune response to vaccines or viral infections. Therefore, we sought to investigate the effects of SIV infection on T cell subsets and NK cells in peripheral and mucosal compartments of SIV-infected rhesus macaques and analyze in the context of virological and immunological outcomes. As previously demonstrated, a pronounced depletion of CD4+ T cells was detected both in peripheral blood and intestinal tissues. A rapid increase in the total frequency of NK cells was observed following the acute phase of SIV infection, suggesting that these NK cells might have contributed to the control of virus replication during this stage. There were no significant differences observed in total NK cells in the gut but the percentage of proliferating NK cells had a significant increase at this stage. Summary: Research studies presented in this dissertation have identified the impact of immune modulation through subclinical viral infections or through mesenchymal stem cell therapy, on the host immune responses to viral infection and vaccines in the SIV-infected rhesus macaque model of AIDS. The study identified a novel functionality of MSC in enhancing anti-viral immunity and highlights an opportunity to boost anti-viral immunity in HIV infection. Our findings on the impact of CMV on dampening anti-viral vaccine immunity has identified one of the mechanisms of immune heterogeneity in vaccine responses at the population level. Collectively, these studies have identified mechanisms that can enhance therapeutic and prevention approaches for HIV infection.
Author: Alekhya Josyula Venkata
Publisher:
ISBN:
Category :
Languages : en
Pages : 101
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Book Description
Antibodies are one of the host's main defences against invading pathogens. There has yet to be a vaccine that can elicit antibodies capable of neutralizing a wide array of circulating Human Immunodeficiency Virus type-1 (HIV-1) strains. The general inability of germline (gl) precursors of these antibodies, termed broadly neutralizing antibodies (bnAbs), to bind recombinant forms of the Env spike used in prospective vaccine formulations has been identified as one of the likely obstacles to achieving a bnAb response by vaccination. The design of antigens that can engage gl precursors of bnAbs, dubbed "gl targeting", is a strategy currently being explored to elicit bnAbs. The VRC01-class of bnAbs, which target the highly conserved CD4 binding site on the HIV Env spike, are attractive templates for vaccine design owing to their tremendous neutralization potency and breadth and common mode of antigen recognition. Here, we investigated a panel of antigens, derived from the 45_01dG5 strain of HIV-1, for their ability to engage VRC01-class gl precursors. Additionally, we assessed their capacity to stimulate T follicular helper (Tfh) cell and B cell responses in C57BL/6 mice after a single immunization, using assays developed with two model immunogens. Specifically, we assessed the influence, on Tfh and B cell responses, of appending a single copy of the PanDR helper epitope (PADRE) to select immunogens. We found that several constructs bind mature and gl-reverted versions of the VRC01 bnAb, as well as one of two VRC01-class precursor antibodies tested here. The immunizations revealed that immunogens with a glycan-masked V3 elicit a very weak Tfh response, which may have led to correspondingly weak B cell responses. Appendage of the single PADRE motif was insufficient to reverse the otherwise weak Tfh cell responses observed with the V3-masked immunogens used here, supporting the need for multiple copies of the motif to adequately provide Tfh cell mediated B cell help. In sum, this work provides insight into the early immune response to priming by HIV-1 candidate immunogens as part of a first phase of explorations toward eliciting VRC01-class bnAbs.
Author: Angus W. Thomson
Publisher: Springer Science & Business Media
ISBN: 9780792368892
Category : Medical
Languages : en
Pages : 534
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Book Description
This work has broad applications in clinical medicine, ranging from prevention and treatment of organ and bone marrow transplant rejection, management of various autoimmune disorders (for example, rheumatoid arthritis), skin disease and asthma. Whereas traditionally only a small repertoire of immunosuppressive agents was available for clinical use, recent discoveries have significantly increased the number of approved agents, resulting in numerous trials to further evaluate their potential. There is also considerable interest in the potential of cell-based therapies (particularly hematopoietic stem and dendritic cell therapy) of allo- and autoimmunity. Important recent advances in the immunotherapy of allergic diseases are also covered in this book. This volume is intended both for practising physicians and surgeons and for biomedical scientists at the graduate/postdoctoral levels, and is designed to provide the theory behind these various approaches to immunosuppression, and to provide state-of-the-art reviews of current developments in each area.
Author: Alireza Minagar
Publisher: Nova Publishers
ISBN: 9781594546105
Category : Medical
Languages : en
Pages : 280
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Book Description
During the past two decades, the world scientific community has witnessed major achievements in our understanding of the pathogenesis of HIV infection of the nervous system and HIV-Associated Dementia (HAD). Despite these giant gains, nervous system involvement during AIDS remains a relentlessly progressive disease with a deadly fate in many cases. This book on NeuroAIDS provides a unique resource for both general neurologists as well as basic neuroscientists with profound interests for research on NeuroAIDS. This book has special emphasis on the mechanisms of disease development and progression of HIV-infected patients with NeuroAIDS. The contributors have provided the readers with comprehensive reviews on clinical manifestations of HAD, mechanisms of HIV entry into the central nervous system, the role of cytokines and chemokines in pathogenesis of NeuroAIDS, drug abuse and NeuroAIDS, virus load in HAD, allostasis in HIV and AIDS, stroke in AIDS patients, and neuroimaging of HIV infection of the central nervous system. In addition, there are chapters on Varicella Zoster virus infection of HIV-seropositive and AIDS patients, as well as the molecular basis for opioids and AIDS virus interactions.
