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Author: Pratima Kunwar
Publisher:
ISBN:
Category :
Languages : en
Pages : 133
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Book Description
The enormity of global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic underscores the urgency to develop a safe, effective and accessible prophylactic AIDS vaccine. Multiple lines of evidence in humans and animal models have shown that HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL) are important in controlling and preventing HIV infection. However, the precise qualities of effective epitope-specific CD8+ CTL responses that may be responsible for control remain unclear. Several vaccine strategies have been designed to elicit CD8+ T cell responses against HIV. Previous T cell based vaccine candidates that have failed to offer protection and HIV control primarily induced HIV-1-specific T cells that targeted variable regions of HIV-1. Genetic studies have shown an association between specific human leukocyte antigens (HLAs), (notably HLA-B*27 and -B*57 allele groups) and slower rates of disease progression in the absence of anti-retroviral therapy (ART). HIV-1-specific CD8+ T cells restricted by these HLA alleles are dominant early in infection in individuals expressing these alleles, and predominantly target conserved regions of Gag. These data suggest that an effective T-cell based immunogen should contain conserved regions of HIV-1 as it will increase the likelihood that CD8+ T cells will recognize incoming viral species of diverse clades and decrease the likelihood of rapid escape variants against the recognized epitopes. We extend these observations to comprehensively identify all CD8+ T cell responses that are elicited during early infection. The central goal of this dissertation is to determine if conservation of the epitopes targeted during early HIV-1-infection play an important role on viral control. Here we demonstrate that individuals possessing CD8+ T cells recognizing conserved epitopes of the virus have lower viral load set point than those recognizing only variable epitopes. Collectively, our results imply that the next-generation of T cell based vaccines should focus on strategies that can induce CD8+ T cell responses specifically to conserved regions of HIV-1.
Author: Pratima Kunwar
Publisher:
ISBN:
Category :
Languages : en
Pages : 133
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Book Description
The enormity of global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic underscores the urgency to develop a safe, effective and accessible prophylactic AIDS vaccine. Multiple lines of evidence in humans and animal models have shown that HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL) are important in controlling and preventing HIV infection. However, the precise qualities of effective epitope-specific CD8+ CTL responses that may be responsible for control remain unclear. Several vaccine strategies have been designed to elicit CD8+ T cell responses against HIV. Previous T cell based vaccine candidates that have failed to offer protection and HIV control primarily induced HIV-1-specific T cells that targeted variable regions of HIV-1. Genetic studies have shown an association between specific human leukocyte antigens (HLAs), (notably HLA-B*27 and -B*57 allele groups) and slower rates of disease progression in the absence of anti-retroviral therapy (ART). HIV-1-specific CD8+ T cells restricted by these HLA alleles are dominant early in infection in individuals expressing these alleles, and predominantly target conserved regions of Gag. These data suggest that an effective T-cell based immunogen should contain conserved regions of HIV-1 as it will increase the likelihood that CD8+ T cells will recognize incoming viral species of diverse clades and decrease the likelihood of rapid escape variants against the recognized epitopes. We extend these observations to comprehensively identify all CD8+ T cell responses that are elicited during early infection. The central goal of this dissertation is to determine if conservation of the epitopes targeted during early HIV-1-infection play an important role on viral control. Here we demonstrate that individuals possessing CD8+ T cells recognizing conserved epitopes of the virus have lower viral load set point than those recognizing only variable epitopes. Collectively, our results imply that the next-generation of T cell based vaccines should focus on strategies that can induce CD8+ T cell responses specifically to conserved regions of HIV-1.
Author: Anne Marie Bet
Publisher:
ISBN:
Category :
Languages : en
Pages : 111
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Book Description
Cryptic epitopes (CE) are a unique set of human leukocyte antigen class I (HLAI)- restricted peptides that are encoded by alternative reading frames (ARFs) of genes. During human immunodeficiency virus-1 (HIV-1) infection, CE translated from either sense or antisense transcripts elicit epitope-specific CD8 T cell responses. Previous studies using simian immunodeficiency virus (SIV)-vaccinated animals have shown that an increased breadth of CD8 T cell responses is correlated with controlling viral replication, therefore stressing the potential clinical benefit of vaccine-induced T cell responses to a diverse set of viral epitopes. Yet, the genetic profiles and immunological significance of CE remain poorly understood. The work presented herein describes the recognition of HIV-1 CE during infection and following vaccination. Using bioinformatic tools, a preliminary analysis of coding strategies for vaccine vectors revealed a striking reduction in the amino acid identity of ARF sequences following codon optimization. I therefore evaluated the induction of T cell responses to CE in recipients of a noncodon-optimized HIV-1 vaccine (MVA/HIV62). My ex vivo analysis showed near-threshold positive responses to CE in both the vaccine and placebo groups. However, in vitro expansion of virus-specific T cells allowed for detection of highmagnitude responses to CE in vaccine but not placebo recipients. These findings represent the first demonstration of vaccine-induced T cell responses to CE in a human clinical trial. As a continuation of my research on novel HIV-1 ARF immunogens, I evaluated the immunogenicity of antigens expressed from a conserved, open reading frame found in an antisense ARF of HIV-1 env, or so called Antisense Protein (ASP). T cell responses to HLA-I-restricted ASP antigens were studied in chronically-infected HIV-1-positive patients. My results showed that ASP-derived epitopes were specifically recognized by CD8 T cells from patients who expressed the appropriate HLA-I molecules. This work provides further evidence for the existence of ASP and indicates that some CE are biomarkers of transcriptionally active viral ARFs. In sum, my dissertation research highlighted the immunological relevance of CE and suggests that future HIV-1 vaccines may be enhanced by prioritizing expression of ARF immunogens to increase to total number of potential T cell targets.
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: Allison Abendroth
Publisher: Springer Science & Business Media
ISBN: 3642127282
Category : Medical
Languages : en
Pages : 382
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Book Description
This book offers a comprehensive review of basic and clinical research on Varicella-zoster Virus, the only human herpesvirus for which vaccines to prevent both primary and recurrent infection are approved.
Author: Guido Silvestri
Publisher: Springer
ISBN: 303002816X
Category : Medical
Languages : en
Pages : 248
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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: Linqi Zhang
Publisher: Springer
ISBN: 981130484X
Category : Medical
Languages : en
Pages : 326
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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: Elnaz Shadabi
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
HIV-1 mutates to escape HLA Class I restricted CD8+ T cells. Positively selected mutations (PSMs) are amino acid substitutions that allow the virus to survive under host immune pressure. However, the impact of PSMs on host clinical outcomes remains unknown. Negative effector (Nef), an accessory protein of HIV-1, enhances the pathogenicity and replication of the virus by down-regulating CD4 and HLA Class I expression from host cell surface to avoid recognition by immune cells, and modification of host cell signal transduction pathways to ensure a persistent state of infection. In both human and macaque models of infection some Nef-specific CD8+ T cell responses that drive viral mutations have been associated with better immune control. In this study, we identified PSMs within HIV-1 Nef, and analyzed their association with host immune selection pressure, and their potential impact on host disease status. We hypothesized that CD8+ T cell epitopes in HIV-1 Nef protein contain PSMs that are associated with different clinical outcomes in the infected host. HIV-1 nef gene was sequenced using 454 sequencing technology from 508 HIV-positive samples of the Pumwani sex-workers cohort of Nairobi, Kenya. PSMs in Nef were identified using bioinformatics tool, Quasi analysis and correlated with disease progression data. Three PSMs were associated with faster CD4 decline (E63D p=0.028, log rank: 4.799; I101V p=0.003, log rank:8.667 and I168M p=0.042, log rank:4.150), while two PSMs were associated with slower CD4 decline (H116N p=0.00011, log rank:14.891 and K182M p=0.03, log rank=4.753). Forty peptides containing a specific PSM were tested with ELISPOT assay, 27 of which were confirmed as CD8+ T cell epitopes. There was no significant difference in the frequency of antigen-specific CD8+ T cells with antiviral intracellular cytokines, their proliferation and exhaustion characteristics between peptides with PSMs associated with different disease progression status. However, the frequency of CD8+ T cells restricted by A*02:01-ILDLWVYNT (IT9-N) epitope, containing a PSM associated with slower CD4 decline, was higher (p0.0001) than CD8+ T cells restricted by A*02:01-ILDLWVYHT (IT9-H) epitope, containing consensus amino acid associated with faster CD4 decline. Identification of PSMs associated with different clinical outcomes and characterization of CD8+ T cell populations specific to these PSM containing epitopes can help to determine better immunogens for an effective HIV-1 vaccine.
Author: Anthony S. Fauci
Publisher: Springer Science & Business Media
ISBN: 3642608671
Category : Medical
Languages : en
Pages : 159
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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: Melissa Herman
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
For three decades, CD8+ T cells have been implicated in the control of HIV, ever since early studies revealed that a temporal correlation exists between the emergence of CD8+ T cells and the decline of viral loads in HIV infection. Subsequently, a large body of research focusing on the impact of CD8+ T cell responses on HIV has been produced. The central aim of this thesis was to investigate the relationship between CD8+ T cells and control of HIV, with a focus on the differences in CD8+ T cell responses to consensus HIV epitopes and their naturally occurring variants, as well as CD8+ T cell-mediated infection inhibition in disease progression groups. Previous work has indicated that mutations in HIV epitopes of just one or two amino acids can have a drastic impact on the resulting CD8+ T cell response. Considering the extreme genetic diversity of the virus, understanding how CD8+ T cell responses differ to these common natural variants is essential when trying to elucidate what the best targets for an HIV vaccine would be. It was hypothesized that CD8+ T cell responses to consensus HIV epitopes, as a consequence of them being more common in nature, would be more frequent, polyfunctional, and proliferative than responses to their less common variants, as well as being associated with better disease outcomes. After assessing these functional parameters in response to four consensus HIV epitopes and their natural variants, this hypothesis was rejected, and it was determined that the consensus status of an epitope could not reliably dictate the resulting CD8+ T cell response. Rather, it seems more likely that the particular epitope being presented, combined with the HLA allele presenting it and the particular TCRs binding to it, have a much larger impact on the CD8+ T cell response. In the course of this study, the Gag TL9 T variant epitope was identified as stimulating a CD8+ T cell response that is considered to be beneficial in HIV infection. Responses to this epitope were also associated with higher CD4 counts, which, taken together, suggests that this epitope has potential for further research as an HIV vaccine target. In the spectrum of HIV infection, there is a significant amount of heterogeneity in disease progression, whereby some individuals progress to disease more slowly, and others, more rapidly. The mechanisms by which this differential disease progression occurs are not completely understood. It was hypothesized that CD8+ T cells from individuals who progress to disease more slowly (long term non- progressors) would be able to inhibit p24 production in-vitro to a higher degree than CD8+ T cells from individuals who progress more rapidly or at a normal rate (RP/NP). This hypothesis was confirmed, as CD8+ T cells from LTNP individuals were significantly better at inhibiting both secreted and intracellular p24 levels than CD8+ T cells from RP/NPs in an in vitro viral inhibition assay. Overall, these studies confirm that CD8+ T cells are important in control of HIV, as indicated by an increased capacity to inhibit p24 in LTNP individuals. However, it is also clear from this work that the role that CD8+ T cells play in HIV infection is complex, and the responses to HIV epitopes can vary greatly.
Author: Kenneth Murphy
Publisher: Garland Science
ISBN: 9780815344575
Category : Medical
Languages : en
Pages :
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Book Description
The Janeway's Immunobiology CD-ROM, Immunobiology Interactive, is included with each book, and can be purchased separately. It contains animations and videos with voiceover narration, as well as the figures from the text for presentation purposes.
