The Experts below are selected from a list of 8847 Experts worldwide ranked by ideXlab platform
Ashley T Haase - One of the best experts on this subject based on the ideXlab platform.
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a role for syndecan 1 and claudin 2 in microbial translocation during hiv 1 infection
2010Co-Authors: Anthony J Smith, Cavan S Reilly, Timothy W Schacker, Ashley T HaaseAbstract:Microbial translocation from the gastrointestinal tract has been implicated in chronic activation of the immune system during progressive HIV-1 infection by ill-defined mechanisms. We recently identified a gene encoding syndecan-1 (SYN1) in microarray studies of HIV-1 infection in Lymphatic Tissues and show here that increased expression of SYN1 in the gut of HIV-1-infected individuals is associated with increased microbial translocation. We further show that: (i) microbial access to SYN1 in the intestinal epithelium could be mediated by compromised barrier function through the up-regulation of claudin-2; (ii) increases in SYN1 and microbial translocation are associated with systemic immune activation; and (iii) SYN1 expression and microbial translocation are inversely correlated with peripheral blood CD4+ T cell counts. We thus propose a new mechanism in which claudin-2 and SYN1 work in concert to enhance microbial translocation across the intestinal epithelial barrier to contribute to chronic immune activation and CD4+ T cell depletion.
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amount of Lymphatic tissue fibrosis in hiv infection predicts magnitude of haart associated change in peripheral cd4 cell count
2005Co-Authors: Timothy W Schacker, Gregory J Beilman, Matthew Larson, Jodie H Taylor, David E Skarda, David Krason, Cavan S Reilly, Ashley T HaaseAbstract:The structure of Lymphatic Tissues is an important component of Lymphatic tissue T-cell homeostasis. Collagen deposition in Lymphatic Tissues (common in HIV infection) disrupts the niche and limits the size of the resident CD4 cell population. In this report we show that a single measurement of Lymphatic tissue collagen predicts the magnitude of recovery of the peripheral CD4 cell pool with HAART (P < 0.001). This suggests that collagen-targeted therapies might be of benefit.
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functional genomic analysis of the response of hiv 1 infected Lymphatic tissue to antiretroviral therapy
2004Co-Authors: Timothy W Schacker, Gregory J Beilman, John V Carlis, Phuong A Nguyen, Ashley T HaaseAbstract:Highly active antiretroviral therapy (HAART) curtails human immunodeficiency virus type 1 (HIV-1) replication in Lymphatic Tissues and partially reverses the pathological damage associated with infection, but the genes that mediate these pathological and reparative processes remain largely unknown. To identify these genes, we used microarrays to profile gene expression in serial lymph node biopsy specimens obtained before and after treatment. We discovered ∼200 treatment-responsive genes, many of them known mediators and moderators of immune activation and defenses, particularly innate defense genes, which, surprisingly, were expressed at all stages of HIV-1 infection. Most of the rest of the treatment-responsive genes we categorized as mediators of trafficking, reformation of active follicles, and tissue repair. We propose a model in which nearly counterbalanced functions of mediators and moderators of immune activation and defenses account for the slow dynamics of HIV-1 infection before treatment. This model suggests that there could be a role for anti-inflammatory agents, alone or in combination with HAART, in treating HIV-1 infection by tipping this balance to mitigate pathology.
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collagen deposition in hiv 1 infected Lymphatic Tissues and t cell homeostasis
2002Co-Authors: Timothy W Schacker, Phuong L Nguyen, Gregory J Beilman, Steven M Wolinsky, Matthew Larson, Cavan S Reilly, Ashley T HaaseAbstract:Lymphatic Tissues (LTs) are structurally organized to promote interaction between antigens, chemokines, growth factors, and lymphocytes to generate an immunologic response and maintain normal-sized populations of CD4+ and CD8+ T cells. Inflammation and tissue remodeling that accompany local innate and adaptive immune responses to HIV-1 replication cause damage to the LT architecture. As a result, normal populations of CD4+ and CD8+ T cells cannot be supported and antigen-lymphocyte interactions are impaired. This conclusion is supported herein following LT sampling before and during anti-HIV therapy in persons with acute, chronic, and late-stage HIV-1 infection. Among seven individuals treated with anti-retroviral therapy (ART) and four individuals deferring therapy we found evidence of significant paracortical T cell zone damage associated with deposition of collagen, the extent of which was inversely correlated with both the size of the LT CD4+ T cell population and the change in peripheral CD4+ T cell count with anti-HIV therapy. The HIV-1–associated inflammatory changes and scarring in LT both limit the ability of the tissue to support and reestablish normal-sized populations of CD4+ T cells and suggest a novel mechanism of T cell depletion that may explain the failure of ART to significantly increase CD4+ T cell populations in some HIV-1–infected persons.
Timothy W Schacker - One of the best experts on this subject based on the ideXlab platform.
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a role for syndecan 1 and claudin 2 in microbial translocation during hiv 1 infection
2010Co-Authors: Anthony J Smith, Cavan S Reilly, Timothy W Schacker, Ashley T HaaseAbstract:Microbial translocation from the gastrointestinal tract has been implicated in chronic activation of the immune system during progressive HIV-1 infection by ill-defined mechanisms. We recently identified a gene encoding syndecan-1 (SYN1) in microarray studies of HIV-1 infection in Lymphatic Tissues and show here that increased expression of SYN1 in the gut of HIV-1-infected individuals is associated with increased microbial translocation. We further show that: (i) microbial access to SYN1 in the intestinal epithelium could be mediated by compromised barrier function through the up-regulation of claudin-2; (ii) increases in SYN1 and microbial translocation are associated with systemic immune activation; and (iii) SYN1 expression and microbial translocation are inversely correlated with peripheral blood CD4+ T cell counts. We thus propose a new mechanism in which claudin-2 and SYN1 work in concert to enhance microbial translocation across the intestinal epithelial barrier to contribute to chronic immune activation and CD4+ T cell depletion.
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the role of secondary Lymphatic tissue in immune deficiency of hiv infection
2008Co-Authors: Timothy W SchackerAbstract:HIV infection is a disease primarily of Lymphatic Tissues, in which most viral replication occurs in CD4 T cells. The most common measures of the impact of HIV infection are made by counting CD4 T cells in peripheral blood. Peripheral blood, however, contains only 2% of the total CD4 cell population in the body and these are typically effector memory cells in transit; the vast majority of CD4 cells reside in the secondary lymphoid Tissues (e.g. lymph nodes and mucosal Lymphatic Tissues) and the impact of HIV replication is most profound on the population residing within these compartments. Within organized follicular aggregates in mucosal Tissues and the very precise structures of lymph nodes most viral replication occurs in the parafollicular T-cell zone, both in primary infection and throughout the course of the disease, such that by the time the patient presents with symptoms of HIV seroconversion approximately 50% of the population is already depleted. Therefore, if we are to understand the pathophysiology and pathogenesis of HIV and its related complications fully, we need to examine the structure and function of secondary lymphoid Tissues before and during HIV infection and before and during HIV treatment. This may provide valuable insights into the underlying pathogenesis of a range of disorders associated with HIV infection, and potentially aid in the development of therapies aimed at emerging complications of long-term HIV infection.
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amount of Lymphatic tissue fibrosis in hiv infection predicts magnitude of haart associated change in peripheral cd4 cell count
2005Co-Authors: Timothy W Schacker, Gregory J Beilman, Matthew Larson, Jodie H Taylor, David E Skarda, David Krason, Cavan S Reilly, Ashley T HaaseAbstract:The structure of Lymphatic Tissues is an important component of Lymphatic tissue T-cell homeostasis. Collagen deposition in Lymphatic Tissues (common in HIV infection) disrupts the niche and limits the size of the resident CD4 cell population. In this report we show that a single measurement of Lymphatic tissue collagen predicts the magnitude of recovery of the peripheral CD4 cell pool with HAART (P < 0.001). This suggests that collagen-targeted therapies might be of benefit.
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functional genomic analysis of the response of hiv 1 infected Lymphatic tissue to antiretroviral therapy
2004Co-Authors: Timothy W Schacker, Gregory J Beilman, John V Carlis, Phuong A Nguyen, Ashley T HaaseAbstract:Highly active antiretroviral therapy (HAART) curtails human immunodeficiency virus type 1 (HIV-1) replication in Lymphatic Tissues and partially reverses the pathological damage associated with infection, but the genes that mediate these pathological and reparative processes remain largely unknown. To identify these genes, we used microarrays to profile gene expression in serial lymph node biopsy specimens obtained before and after treatment. We discovered ∼200 treatment-responsive genes, many of them known mediators and moderators of immune activation and defenses, particularly innate defense genes, which, surprisingly, were expressed at all stages of HIV-1 infection. Most of the rest of the treatment-responsive genes we categorized as mediators of trafficking, reformation of active follicles, and tissue repair. We propose a model in which nearly counterbalanced functions of mediators and moderators of immune activation and defenses account for the slow dynamics of HIV-1 infection before treatment. This model suggests that there could be a role for anti-inflammatory agents, alone or in combination with HAART, in treating HIV-1 infection by tipping this balance to mitigate pathology.
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collagen deposition in hiv 1 infected Lymphatic Tissues and t cell homeostasis
2002Co-Authors: Timothy W Schacker, Phuong L Nguyen, Gregory J Beilman, Steven M Wolinsky, Matthew Larson, Cavan S Reilly, Ashley T HaaseAbstract:Lymphatic Tissues (LTs) are structurally organized to promote interaction between antigens, chemokines, growth factors, and lymphocytes to generate an immunologic response and maintain normal-sized populations of CD4+ and CD8+ T cells. Inflammation and tissue remodeling that accompany local innate and adaptive immune responses to HIV-1 replication cause damage to the LT architecture. As a result, normal populations of CD4+ and CD8+ T cells cannot be supported and antigen-lymphocyte interactions are impaired. This conclusion is supported herein following LT sampling before and during anti-HIV therapy in persons with acute, chronic, and late-stage HIV-1 infection. Among seven individuals treated with anti-retroviral therapy (ART) and four individuals deferring therapy we found evidence of significant paracortical T cell zone damage associated with deposition of collagen, the extent of which was inversely correlated with both the size of the LT CD4+ T cell population and the change in peripheral CD4+ T cell count with anti-HIV therapy. The HIV-1–associated inflammatory changes and scarring in LT both limit the ability of the tissue to support and reestablish normal-sized populations of CD4+ T cells and suggest a novel mechanism of T cell depletion that may explain the failure of ART to significantly increase CD4+ T cell populations in some HIV-1–infected persons.
A T Haase - One of the best experts on this subject based on the ideXlab platform.
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population biology of hiv 1 infection viral and cd4 t cell demographics and dynamics in Lymphatic Tissues
1999Co-Authors: A T HaaseAbstract:▪ Abstract Human immunodeficiency virus-1 (HIV-1) is usually transmitted through sexual contact and in the very early stages of infection establishes a persistent infection in Lymphatic Tissues (LT). Virus is produced and stored at this site in a dynamic process that slowly depletes the immune system of CD4+ T cells, setting the stage for AIDS. In this review, I describe the changes in viral and CD4+ T cell populations in LT over the course of infection and after treatment. I present recent evidence that productively infected CD4+ T cells play an important role in establishing persistent infection from the onset, and that the LT are the major reservoir where virus is produced and stored on follicular dendritic cells (FDCs). I discuss the methods used to define the size of viral and CD4+ T cell populations in LT and the nature of virus-host cell interactions in vivo. These experimental approaches have identified populations of latently and chronically infected cells in which virus can elude host defenses, ...
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population biology of hiv 1 infection viral and cd4 t cell demographics and dynamics in Lymphatic Tissues
1999Co-Authors: A T HaaseAbstract:Human immunodeficiency virus-1 (HIV-1) is usually transmitted through sexual contact and in the very early stages of infection establishes a persistent infection in Lymphatic Tissues (LT). Virus is produced and stored at this site in a dynamic process that slowly depletes the immune system of CD4+ T cells, setting the stage for AIDS. In this review, I describe the changes in viral and CD4+ T cell populations in LT over the course of infection and after treatment. I present recent evidence that productively infected CD4+ T cells play an important role in establishing persistent infection from the onset, and that the LT are the major reservoir where virus is produced and stored on follicular dendritic cells (FDCs). I discuss the methods used to define the size of viral and CD4+ T cell populations in LT and the nature of virus-host cell interactions in vivo. These experimental approaches have identified populations of latently and chronically infected cells in which virus can elude host defenses, perpetuate infection, and escape eradication by highly active antiretroviral treatment (HAART). I discuss the dramatic impact of HAART on suppressing virus production, reducing the pool of stored virus, and restoring CD4+ T cell populations. I discuss the contributions of thymopoiesis and other renewal mechanisms, Lymphatic homeostasis and trafficking to these changes in CD4+ T cell populations in LT, and conclude with a model of immune depletion and repopulation based on the limited regenerative capacity of the adult and the uncompensated losses of productively infected cells that treatment stems. The prediction of this model is that immune regeneration will be slow, variable, and partial. It is nonetheless encouraging to know that even in late stages of infection, control of active replication of HIV-1 provides an opportunity for the immune system to recover from the injuries inflicted by infection.
Gregory J Beilman - One of the best experts on this subject based on the ideXlab platform.
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large number of rebounding founder hiv variants emerge from multifocal infection in Lymphatic Tissues after treatment interruption
2015Co-Authors: Meghan K Rothenberger, Gregory J Beilman, Courtney V Fletcher, Stephen W Wietgrefe, Jeffrey G Chipman, Alexander Khoruts, Jacob D Estes, Brandon F Keele, Jodi Anderson, Samuel P CallistoAbstract:Antiretroviral therapy (ART) suppresses HIV replication in most individuals but cannot eradicate latently infected cells established before ART was initiated. Thus, infection rebounds when treatment is interrupted by reactivation of virus production from this reservoir. Currently, one or a few latently infected resting memory CD4 T cells are thought be the principal source of recrudescent infection, but this estimate is based on peripheral blood rather than lymphoid Tissues (LTs), the principal sites of virus production and persistence before initiating ART. We, therefore, examined lymph node (LN) and gut-associated lymphoid tissue (GALT) biopsies from fully suppressed subjects, interrupted therapy, monitored plasma viral load (pVL), and repeated biopsies on 12 individuals as soon as pVL became detectable. Isolated HIV RNA-positive (vRNA+) cells were detected by in situ hybridization in LTs obtained before interruption in several patients. After interruption, multiple foci of vRNA+ cells were detected in 6 of 12 individuals as soon as pVL was measureable and in some subjects, in more than one anatomic site. Minimal estimates of the number of rebounding/founder (R/F) variants were determined by single-gene amplification and sequencing of viral RNA or DNA from peripheral blood mononuclear cells and plasma obtained at or just before viral recrudescence. Sequence analysis revealed a large number of R/F viruses representing recrudescent viremia from multiple sources. Together, these findings are consistent with the origins of recrudescent infection by reactivation from many latently infected cells at multiple sites. The inferred large pool of cells and sites to rekindle recrudescent infection highlights the challenges in eradicating HIV.
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amount of Lymphatic tissue fibrosis in hiv infection predicts magnitude of haart associated change in peripheral cd4 cell count
2005Co-Authors: Timothy W Schacker, Gregory J Beilman, Matthew Larson, Jodie H Taylor, David E Skarda, David Krason, Cavan S Reilly, Ashley T HaaseAbstract:The structure of Lymphatic Tissues is an important component of Lymphatic tissue T-cell homeostasis. Collagen deposition in Lymphatic Tissues (common in HIV infection) disrupts the niche and limits the size of the resident CD4 cell population. In this report we show that a single measurement of Lymphatic tissue collagen predicts the magnitude of recovery of the peripheral CD4 cell pool with HAART (P < 0.001). This suggests that collagen-targeted therapies might be of benefit.
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functional genomic analysis of the response of hiv 1 infected Lymphatic tissue to antiretroviral therapy
2004Co-Authors: Timothy W Schacker, Gregory J Beilman, John V Carlis, Phuong A Nguyen, Ashley T HaaseAbstract:Highly active antiretroviral therapy (HAART) curtails human immunodeficiency virus type 1 (HIV-1) replication in Lymphatic Tissues and partially reverses the pathological damage associated with infection, but the genes that mediate these pathological and reparative processes remain largely unknown. To identify these genes, we used microarrays to profile gene expression in serial lymph node biopsy specimens obtained before and after treatment. We discovered ∼200 treatment-responsive genes, many of them known mediators and moderators of immune activation and defenses, particularly innate defense genes, which, surprisingly, were expressed at all stages of HIV-1 infection. Most of the rest of the treatment-responsive genes we categorized as mediators of trafficking, reformation of active follicles, and tissue repair. We propose a model in which nearly counterbalanced functions of mediators and moderators of immune activation and defenses account for the slow dynamics of HIV-1 infection before treatment. This model suggests that there could be a role for anti-inflammatory agents, alone or in combination with HAART, in treating HIV-1 infection by tipping this balance to mitigate pathology.
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collagen deposition in hiv 1 infected Lymphatic Tissues and t cell homeostasis
2002Co-Authors: Timothy W Schacker, Phuong L Nguyen, Gregory J Beilman, Steven M Wolinsky, Matthew Larson, Cavan S Reilly, Ashley T HaaseAbstract:Lymphatic Tissues (LTs) are structurally organized to promote interaction between antigens, chemokines, growth factors, and lymphocytes to generate an immunologic response and maintain normal-sized populations of CD4+ and CD8+ T cells. Inflammation and tissue remodeling that accompany local innate and adaptive immune responses to HIV-1 replication cause damage to the LT architecture. As a result, normal populations of CD4+ and CD8+ T cells cannot be supported and antigen-lymphocyte interactions are impaired. This conclusion is supported herein following LT sampling before and during anti-HIV therapy in persons with acute, chronic, and late-stage HIV-1 infection. Among seven individuals treated with anti-retroviral therapy (ART) and four individuals deferring therapy we found evidence of significant paracortical T cell zone damage associated with deposition of collagen, the extent of which was inversely correlated with both the size of the LT CD4+ T cell population and the change in peripheral CD4+ T cell count with anti-HIV therapy. The HIV-1–associated inflammatory changes and scarring in LT both limit the ability of the tissue to support and reestablish normal-sized populations of CD4+ T cells and suggest a novel mechanism of T cell depletion that may explain the failure of ART to significantly increase CD4+ T cell populations in some HIV-1–infected persons.
Cavan S Reilly - One of the best experts on this subject based on the ideXlab platform.
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persistent hiv 1 replication is associated with lower antiretroviral drug concentrations in Lymphatic Tissues
2014Co-Authors: Courtney V Fletcher, Kathryn Staskus, Stephen W Wietgrefe, Meghan K Rothenberger, Cavan S Reilly, Jeffrey G Chipman, Greg J Beilman, Alexander Khoruts, Ann Thorkelson, Thomas E SchmidtAbstract:Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in Lymphatic Tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.
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a role for syndecan 1 and claudin 2 in microbial translocation during hiv 1 infection
2010Co-Authors: Anthony J Smith, Cavan S Reilly, Timothy W Schacker, Ashley T HaaseAbstract:Microbial translocation from the gastrointestinal tract has been implicated in chronic activation of the immune system during progressive HIV-1 infection by ill-defined mechanisms. We recently identified a gene encoding syndecan-1 (SYN1) in microarray studies of HIV-1 infection in Lymphatic Tissues and show here that increased expression of SYN1 in the gut of HIV-1-infected individuals is associated with increased microbial translocation. We further show that: (i) microbial access to SYN1 in the intestinal epithelium could be mediated by compromised barrier function through the up-regulation of claudin-2; (ii) increases in SYN1 and microbial translocation are associated with systemic immune activation; and (iii) SYN1 expression and microbial translocation are inversely correlated with peripheral blood CD4+ T cell counts. We thus propose a new mechanism in which claudin-2 and SYN1 work in concert to enhance microbial translocation across the intestinal epithelial barrier to contribute to chronic immune activation and CD4+ T cell depletion.
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amount of Lymphatic tissue fibrosis in hiv infection predicts magnitude of haart associated change in peripheral cd4 cell count
2005Co-Authors: Timothy W Schacker, Gregory J Beilman, Matthew Larson, Jodie H Taylor, David E Skarda, David Krason, Cavan S Reilly, Ashley T HaaseAbstract:The structure of Lymphatic Tissues is an important component of Lymphatic tissue T-cell homeostasis. Collagen deposition in Lymphatic Tissues (common in HIV infection) disrupts the niche and limits the size of the resident CD4 cell population. In this report we show that a single measurement of Lymphatic tissue collagen predicts the magnitude of recovery of the peripheral CD4 cell pool with HAART (P < 0.001). This suggests that collagen-targeted therapies might be of benefit.
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collagen deposition in hiv 1 infected Lymphatic Tissues and t cell homeostasis
2002Co-Authors: Timothy W Schacker, Phuong L Nguyen, Gregory J Beilman, Steven M Wolinsky, Matthew Larson, Cavan S Reilly, Ashley T HaaseAbstract:Lymphatic Tissues (LTs) are structurally organized to promote interaction between antigens, chemokines, growth factors, and lymphocytes to generate an immunologic response and maintain normal-sized populations of CD4+ and CD8+ T cells. Inflammation and tissue remodeling that accompany local innate and adaptive immune responses to HIV-1 replication cause damage to the LT architecture. As a result, normal populations of CD4+ and CD8+ T cells cannot be supported and antigen-lymphocyte interactions are impaired. This conclusion is supported herein following LT sampling before and during anti-HIV therapy in persons with acute, chronic, and late-stage HIV-1 infection. Among seven individuals treated with anti-retroviral therapy (ART) and four individuals deferring therapy we found evidence of significant paracortical T cell zone damage associated with deposition of collagen, the extent of which was inversely correlated with both the size of the LT CD4+ T cell population and the change in peripheral CD4+ T cell count with anti-HIV therapy. The HIV-1–associated inflammatory changes and scarring in LT both limit the ability of the tissue to support and reestablish normal-sized populations of CD4+ T cells and suggest a novel mechanism of T cell depletion that may explain the failure of ART to significantly increase CD4+ T cell populations in some HIV-1–infected persons.
