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1.
Caroline S. Fernandez Angela C. Chan Konstantinos Kyparissoudis Robert De Rose Dale I. Godfrey Stephen J. Kent 《Journal of virology》2009,83(4):1617-1624
NKT cells are a specialized population of T lymphocytes that have an increasingly recognized role in immunoregulation, including controlling the response to viral infections. The characteristics of NKT cells in the peripheral blood of macaques during simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (HIV) (SHIV) infection were assessed. NKT cells comprised a mean of 0.19% of peripheral blood lymphocytes across the 64 uninfected macaques studied. Although the range in the percentages of NKT cells was large (0 to 2.2%), levels were stable over time within individual macaques without SIV/SHIV infection. The majority of NKT cells in macaques were CD4+ (on average 67%) with smaller populations being CD8+ (21%) and CD4/CD8 double positive (13%). A precipitous decline in CD4+ NKT cells occurred in all six macaques infected with CXCR4-tropic SHIVmn229 early after infection, with a concomitant rise in CD8+ NKT cells in some animals. The depletion of CD4+ NKT cells was tightly correlated with the depletion of total CD4+ T cells. R5-tropic SIVmac251 infection of macaques resulted in a slower and more variable decline in CD4+ NKT cells, with animals that were able to control SIV virus levels maintaining higher levels of CD4+ NKT cells. An inverse correlation between the depletion of total and CD4+ NKT cells and SIV viral load during chronic infection was observed. Our results demonstrate the infection-driven depletion of peripheral CD4+ NKT cells during both SHIV and SIV infection of macaques. Further studies of the implications of the loss of NKT cell subsets in the pathogenesis of HIV disease are needed. 相似文献
2.
Gastrointestinal T Lymphocytes Retain High Potential for Cytokine Responses but Have Severe CD4+ T-Cell Depletion at All Stages of Simian Immunodeficiency Virus Infection Compared to Peripheral Lymphocytes
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Zeljka Smit-McBride Joseph J. Mattapallil Michael McChesney David Ferrick Satya Dandekar 《Journal of virology》1998,72(8):6646-6656
Gastrointestinal complications in human immunodeficiency virus (HIV) infection are indicative of impaired intestinal mucosal immune system. We used simian immunodeficiency virus (SIV)-infected rhesus macaques as an animal model for HIV to determine pathogenic effects of SIV on intestinal T lymphocytes. Intestinal CD4+ T-cell depletion and the potential for cytokine responses were examined during SIV infection and compared with results for lymphocytes from lymph nodes and blood. Flow cytometric analysis demonstrated severe depletion of CD4+CD8− single-positive T cells and CD4+CD8+ double-positive T cells in intestinal lamina propria lymphocytes (LPL) and intraepithelial lymphocytes (IEL) during primary SIV infection which persisted through the entire course of SIV infection. In contrast, CD4+ T-cell depletion was gradual in peripheral lymph nodes and blood. Flow cytometric analysis of intracellular gamma interferon (IFN-γ) and interleukin-4 (IL-4) production following short-term mitogenic activation revealed that LPL retained same or higher capacity for IFN-γ production in all stages of SIV infection compared to uninfected controls, whereas peripheral blood mononuclear cells displayed a gradual decline. The CD8+ T cells were the major producers of IFN-γ. There was no detectable change in the frequency of IL-4-producing cells in both LPL and peripheral blood mononuclear cells. Thus, severe depletion of CD4+ LPL and IEL in primary SIV infection accompanied by altered cytokine responses may reflect altered T-cell homeostasis in intestinal mucosa. This could be a mechanism of SIV-associated enteropathy and viral pathogenesis. Dynamic changes in intestinal T lymphocytes were not adequately represented in peripheral lymph nodes or blood. 相似文献
3.
Intestinal Intraepithelial Lymphocytes Are Primed for Gamma Interferon and MIP-1β Expression and Display Antiviral Cytotoxic Activity despite Severe CD4+ T-Cell Depletion in Primary Simian Immunodeficiency Virus Infection
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Joseph J. Mattapallil Zeljka Smit-McBride Michael McChesney Satya Dandekar 《Journal of virology》1998,72(8):6421-6429
Intraepithelial lymphocytes (IEL) are a critical effector component of the gut-associated lymphoid tissue (GALT) and play an important role in mucosal immunity as well as in the maintenance of the epithelial cell integrity and barrier function. The objective of this study was to determine whether simian immunodeficiency virus (SIV) infection of rhesus macaques would cause alterations in the immunophenotypic profiles of IEL and their mitogen-specific cytokine (gamma interferon [IFN-γ] and MIP-1β) responses (by flow cytometry) and virus-specific cytotoxic T-cell (CTL) activity (by the chromium release assay). Virally infected IEL were detected through the entire course of SIV infection by in situ hybridization. Severe depletion of CD4+ single-positive and CD4+CD8+ double-positive T cells occurred early in primary SIV infection, which was coincident with an increased prevalence of CD8+ T cells. This was in contrast to a gradual depletion of CD4+ T cells in peripheral blood. The CD8+ IEL were the primary producers of IFN-γ and MIP-1β and were found to retain their potential to produce both IFN-γ and MIP-1β through the entire course of SIV infection. SIV-specific CTL activity was detected in primary IEL at 1, 2, and 4 weeks post-SIV infection. These results demonstrated that IEL may be involved in generating antiviral immune responses early in SIV infection and in suppressing viral infection thereafter. Alterations in homeostasis in epithelia due to severe CD4+ T-cell depletion accompanied by changes in the cytokine and chemokine production by IEL may play a role in the enteropathogenesis of SIV infection. 相似文献
4.
CD4+ T-Lymphocyte Depletion in Human Lymphoid Tissue Ex Vivo Is Not Induced by Noninfectious Human Immunodeficiency Virus Type 1 Virions
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A. W. Sylwester J.-C. Grivel W. Fitzgerald J. L. Rossio J. D. Lifson L. B. Margolis 《Journal of virology》1998,72(11):9345-9347
We tested infectious human immunodeficiency virus type 1 (HIV-1), noninfectious but conformationally authentic inactivated whole HIV-1 virions, and purified gp120 for the ability to induce depletion of CD4+ T cells in human lymphoid tissues ex vivo. Infectious CXCR4-tropic HIV-1, but not matched inactivated virions or gp120, mediated CD4+ T-cell depletion, consistent with mechanisms requiring productive infection. 相似文献
5.
Asymptomatic Simian Immunodeficiency Virus Infection Decreases Blood CD4+ T Cells by Accumulating Recirculating Lymphocytes in the Lymphoid Tissues
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Declining blood CD4+ T-cell counts mark the progress of simian immunodeficiency virus (SIV) disease in macaques and model the consequences of untreated human immunodeficiency virus infection in humans. However, blood lymphocytes are only a fraction of the recirculating lymphocyte pool, and their numbers are affected by cell synthesis, cell depletion, and distribution among blood and lymphoid tissue compartments. Asymptomatic, SIV-infected macaques maintained constant and nearly normal numbers of recirculating lymphocytes despite the decline in CD4+ T-cell counts. Substantial depletion was detected only when blood CD4+ T-cell counts fell below 300/μl. In asymptomatic animals, changes in CD4+ T-cell distribution were more important than lymphocyte depletion for controlling the blood cell levels. 相似文献
6.
Elite suppressors (ES) are human immunodeficiency virus type 1 (HIV-1)-infected patients who maintain viral loads of <50 copies/ml without treatment. The observation that the HLA-B*57 allele is overrepresented in these patients implies that HIV-1-specific CD8+ T cells play a key role in suppressing viral replication. We have previously shown that while CD8+ T-cell escape mutations are rarely seen in proviral Gag sequences in resting CD4+ T cells from peripheral blood, they are present in every clone amplified from the low levels of free virus in the plasma of HLA-B*57+ ES. In this study, we compared the pattern of mutations in Nef sequences amplified from peripheral blood CD4+ T cells and from plasma virus. We show that Nef mutations are present in plasma virus but are rare in the cellular sequences and provide evidence that these plasma Nef variants represent novel escape mutants. The results provide further evidence of CD8+ T-cell-mediated selective pressure on plasma virus in ES and suggest that there must be ongoing HIV-1 replication in spite of the very low viral loads seen for these patients. 相似文献
7.
Kolli D Bataki EL Spetch L Guerrero-Plata A Jewell AM Piedra PA Milligan GN Garofalo RP Casola A 《Journal of virology》2008,82(17):8560-8569
Human metapneumovirus (hMPV), a member of the family Paramyxoviridae, is a leading cause of lower respiratory tract infections in children, the elderly, and immunocompromised patients. Virus- and host-specific mechanisms of pathogenesis and immune protection are not fully understood. By an intranasal inoculation model, we show that hMPV-infected BALB/c mice developed clinical disease, including airway obstruction and hyperresponsiveness (AHR), along with histopathologic evidence of lung inflammation and viral replication. hMPV infection protected mice against subsequent viral challenge, as demonstrated by undetectable viral titers, lack of body weight loss, and a significant reduction in the level of lung inflammation. No cross-protection with other paramyxoviruses, such as respiratory syncytial virus, was observed. T-lymphocyte depletion studies showed that CD4+ and CD8+ T cells cooperate synergistically in hMPV eradication during primary infection, but CD4+ more than CD8+ T cells also enhanced clinical disease and lung pathology. Concurrent depletion of CD4+ and CD8+ T cells completely blocked airway obstruction as well as AHR. Despite impaired generation of neutralizing anti-hMPV antibodies in the absence of CD4+ T cells, mice had undetectable viral replication after hMPV challenge and were protected from clinical disease, suggesting that protection can be provided by an intact CD8+ T-cell compartment. Whether these findings have implications for naturally acquired human infections remains to be determined. 相似文献
8.
Radziewicz H Ibegbu CC Hon H Osborn MK Obideen K Wehbi M Freeman GJ Lennox JL Workowski KA Hanson HL Grakoui A 《Journal of virology》2008,82(20):9808-9822
A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8+ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8+ T cells during the acute and chronic stages of infection. Although HCV-specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8+ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8+ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the “death phase” of HCV-specific CD8+ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections. 相似文献
9.
Jung Joo Hong Matthew R. Reynolds Teresa L. Mattila Aaron Hage David I. Watkins Christopher J. Miller Pamela J. Skinner 《PloS one》2009,4(1)
CD8 T cells play an important role in controlling viral infections. We investigated the in situ localization of simian immunodeficiency virus (SIV)-specific T cells in lymph and genital tissues from SIV-infected macaques using MHC-class I tetramers. The majority of tetramer-binding cells localized in T cell zones and were CD8+. Curiously, small subpopulations of tetramer-binding cells that had little to no surface CD8 were detected in situ both early and late post-infection, and in both vaginally and rectally inoculated macaques. These tetramer+CD8low/− cells were more often localized in apparent B cell follicles relative to T cell zones and more often found near or within the genital epithelium than the submucosa. Cells analyzed by flow cytometry showed similar populations of cells. Further immunohistological characterization revealed small populations of tetramer+CD20− cells inside B cell follicles and that tetramer+ cells did not stain with γδ-TCR nor CD4 antibodies. Negative control tetramer staining indicated that tetramer+CD8low/− cells were not likely NK cells non-specifically binding to MHC tetramers. These findings have important implications for SIV-specific and other antigen-specific T cell function in these specific tissue locations, and suggest a model in which antigen-specific CD8+ T cells down modulate CD8 upon entering B cell follicles or the epithelial layer of tissues, or alternatively a model in which only antigen-specific CD8 T cells that down-modulate CD8 can enter B cell follicles or the epithelium. 相似文献
10.
FoxP3+ CD25+ CD8+ T-cell induction during primary simian immunodeficiency virus infection in cynomolgus macaques correlates with low CD4+ T-cell activation and high viral load
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Karlsson I Malleret B Brochard P Delache B Calvo J Le Grand R Vaslin B 《Journal of virology》2007,81(24):13444-13455
The early immune response fails to prevent the establishment of chronic human immunodeficiency virus (HIV) infection but may influence viremia during primary infection, thereby possibly affecting long-term disease progression. CD25+ FoxP3+ regulatory T cells may contribute to HIV/simian immunodeficiency virus (SIV) pathogenesis by suppressing efficient antiviral responses during primary infection, favoring high levels of viral replication and the establishment of chronic infection. In contrast, they may decrease immune activation during chronic infection. CD4+ regulatory T cells have been studied in the most detail, but CD8+ CD25+ FoxP3+ T cells also have regulatory properties. We monitored the dynamics of CD25+ FoxP3+ T cells during primary and chronic SIVmac251 infection in cynomolgus macaques. The number of peripheral CD4+ CD25+ FoxP3+ T cells paralleled that of memory CD4+ T cells, with a rapid decline during primary infection followed by a rebound to levels just below baseline and gradual depletion during the course of infection. No change in the proportion of CD25+ FoxP3+ T cells was observed in peripheral lymph nodes. A small number of CD4+ CD25+ FoxP3+ T cells at set point was associated with a high plasma viral load. In contrast, peripheral CD8+ CD25+ FoxP3+ T cells were induced a few days after peak plasma viral load during primary infection. The number of these cells was positively correlated with viral load and negatively correlated with CD4+ T-cell activation, SIV antigen-specific proliferative responses during primary infection, and plasma viral load at set point, with large numbers of CD8+ CD25+ FoxP3+ T cells being indicative of a poor prognosis. 相似文献
11.
Predominance of HLA-Restricted Cytotoxic T-Lymphocyte Responses to Serotype-Cross-Reactive Epitopes on Nonstructural Proteins following Natural Secondary Dengue Virus Infection 总被引:5,自引:1,他引:4
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Anuja Mathew Ichiro Kurane Sharone Green Henry A. F. Stephens David W. Vaughn Siripen Kalayanarooj Saroj Suntayakorn Dasnayanee Chandanayingyong Francis A. Ennis Alan L. Rothman 《Journal of virology》1998,72(5):3999-4004
We examined the memory cytotoxic T-lymphocytic (CTL) responses of peripheral blood mononuclear cells (PBMC) obtained from patients in Thailand 12 months after natural symptomatic secondary dengue virus infection. In all four patients analyzed, CTLs were detected in bulk culture PBMC against nonstructural dengue virus proteins. Numerous CD4+ and CD8+ CTL lines were generated from the bulk cultures of two patients, KPP94-037 and KPP94-024, which were specific for NS1.2a (NS1 and NS2a collectively) and NS3 proteins, respectively. All CTL lines derived from both patients were cross-reactive with other serotypes of dengue virus. The CD8+ NS1.2a-specific lines from patient KPP94-037 were HLA B57 restricted, and the CD8+ NS3-specific lines from patient KPP94-024 were HLA B7 restricted. The CD4+ CTL lines from patient KPP94-037 were HLA DR7 restricted. A majority of the CD8+ CTLs isolated from patient KPP94-024 were found to recognize amino acids 221 to 232 on NS3. These results demonstrate that in Thai patients after symptomatic secondary natural dengue infections, CTLs are mainly directed against nonstructural proteins and are broadly cross-reactive. 相似文献
12.
Amanda M. Schell Erica L. Granger Frank Koczot Matthew A. Fischer Christopher C. Norbury 《Journal of virology》2010,84(7):3586-3594
CD8+ T cells (TCD8+) play a crucial role in immunity to viruses. Antiviral TCD8+ are initially activated by recognition of major histocompatibility complex (MHC) class I-peptide complexes on the surface of professional antigen-presenting cells (pAPC). Migration of pAPC from the site of infection to secondary lymphoid organs is likely required during a natural infection. Migrating pAPC can be directly infected with virus or may internalize antigen derived from virus-infected cells. The use of experimental virus infections to assess the requirement for pAPC migration in initiation of TCD8+ responses has proven difficult to interpret because injected virus can readily drain to secondary lymphoid organs without the need for cell-mediated transport. To overcome this ambiguity, we examined the generation of antigen-specific TCD8+ after immunization with recombinant adenoviruses that express antigen driven by skin-specific or ubiquitous promoters. We show that the induction of TCD8+ in response to tissue-targeted antigen is less efficient than the response to ubiquitously expressed antigen and that the resulting TCD8+ fail to clear all target cells pulsed with the antigenic peptide. This failure to prime a fully functional TCD8+ response results from a reduced period of priming to peripherally expressed antigen versus ubiquitously expressed antigen and correlated with a brief burst of pAPC migration from the skin, a requirement for induction of the response to peripheral antigen. These results indicate that a reduced duration of pAPC migration after virus infection likely reduces the amplitude of the TCD8+ response, allowing persistence of the peripheral virus.The induction of effector CD8+ T cells (TCD8+) is a vital step in the eradication or control of many viral infections. The induction of antiviral TCD8+ requires the presentation of virally derived peptides in complex with major histocompatibility complex (MHC) class I on the surface of specialized professional antigen-presenting cells (pAPC), most commonly a subset of dendritic cells (DC) that bear the CD8α chain (1, 29). The CD8α+ DC reside only in secondary lymphoid organs and not in the tissues, implying that cell-mediated transport or drainage of virus particles to a lymph node is required for initiation of a TCD8+ response. Partial inhibition of DC migration from the skin can impair the initiation of a TCD8+ response (2). After influenza infection in the lungs, there is a burst of DC migration, followed by a refractory period in which no DC migration occurs (19). The functional consequences of this refractory period of DC migration have not been explored.A number of viruses, particularly human papillomaviruses, infect the skin and are ignored by the immune response for extended periods of time (31). We sought to explore the possibility that, after a low-level peripheral virus infection of the skin, changes in DC migration may limit the availability of antigen in the draining lymph node and thus the induction of a TCD8+ response. There are a number of confounding factors that make the study of DC migration in the initiation of an antiviral TCD8+ response difficult. Virus particles may directly drain to the lymph node within seconds (11, 13, 25). In addition, many viruses will alter DC functions, including migration, after infection of the DC itself. This may occur via specific viral modulation of DC function (16) or via nonspecific shut down of host protein synthesis (26), both of which will affect migration. Thus, it is often not possible to distinguish between the effects of virus infection upon DC migration, drainage of virus directly to the lymph node, and the natural response that follows migration of DC responding to a peripheral virus infection.There is currently no mouse model of a peripheral virus infection that is confined to the skin, as no natural mouse papillomavirus has ever been isolated. Therefore, to address these issues, we have made use of another small DNA virus, namely, an adenovirus vector that is replication deficient (rAd). These vectors express influenza virus nucleoprotein (NP) under the control of a ubiquitous (cytomegalovirus [CMV] immediate-early) or tissue-targeted promoter (K14, targeted to keratinocytes, the site of papillomavirus replication). Antigen driven by the K14 promoter is expressed only in skin cells, so only uninfected DC can present antigen in this system, removing the need to account for modulation of the function of virus-infected DC.We demonstrate that when antigen is expressed in only keratinocytes in the skin, the efficiency of TCD8+ induction is reduced and the time period for which antigen is available to prime effector cells is reduced dramatically. DC-mediated transport is required for antigen to reach the lymph node where a TCD8+ response is initiated. The reduced time period of antigen presentation is the result of a transient blockade in DC migration from the site of infection. The blockade in DC migration reduced the delivery of viral antigen to the lymph node needed to induce a TCD8+ response. The resulting TCD8+ response to peripheral viral antigen is not capable of clearing all target cells presenting a viral peptide, thus allowing the persistence of peripheral virus-infected cells. These results provide a potential mechanism for the long-term evasion of the immune response by papillomaviruses following natural infection and also have important implications for tissue targeted gene therapy vectors. 相似文献
13.
In primary infection, CD8+ T cells are important for clearance of infectious herpes simplex virus (HSV) from sensory ganglia. In this study, evidence of CD4+ T-cell-mediated clearance of infectious HSV type 1 (HSV-1) from neural tissues was also detected. In immunocompetent mice, HSV-specific CD4+ T cells were present in sensory ganglia and spinal cords coincident with HSV-1 clearance from these sites and remained detectable at least 8 months postinfection. Neural CD4+ T cells isolated at the peak of neural infection secreted gamma interferon, tumor necrosis factor alpha, interleukin-2 (IL-2), or IL-4 after stimulation with HSV antigen. HSV-1 titers in neural tissues were greatly reduced over time in CD8+ T-cell-deficient and CD8+ T-cell-depleted mice, suggesting that CD4+ T cells could mediate clearance of HSV-1 from neural tissue. To examine possible mechanisms by which CD4+ T cells resolved neural infection, CD8+ T cells were depleted from perforin-deficient or FasL-defective mice. Clearance of infectious virus from neural tissues was not significantly different in perforin-deficient or FasL-defective mice compared to wild-type mice. Further, in spinal cords and brains after vaginal HSV-1 challenge of chimeric mice expressing both perforin and Fas or neither perforin nor Fas, virus titers were significantly lower than in control mice. Thus, perforin and Fas were not required for clearance of infectious virus from neural tissues. These results suggest that HSV-specific CD4+ T cells are one component of a long-term immune cell presence in neural tissues following genital HSV-1 infection and play a role in clearance of infectious HSV-1 at neural sites, possibly via a nonlytic mechanism. 相似文献
14.
Nichole R. Klatt Emi Shudo Alex M. Ortiz Jessica C. Engram Mirko Paiardini Benton Lawson Michael D. Miller James Else Ivona Pandrea Jacob D. Estes Cristian Apetrei Joern E. Schmitz Ruy M. Ribeiro Alan S. Perelson Guido Silvestri 《PLoS pathogens》2010,6(1)
While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication. 相似文献
15.
Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections 总被引:7,自引:0,他引:7
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Meier UC Owen RE Taylor E Worth A Naoumov N Willberg C Tang K Newton P Pellegrino P Williams I Klenerman P Borrow P 《Journal of virology》2005,79(19):12365-12374
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause clinically important persistent infections. The effects of virus persistence on innate immunity, including NK cell responses, and the underlying mechanisms are not fully understood. We examined the frequency, phenotype, and function of peripheral blood CD3− CD56+ NK subsets in HIV+ and HCV+ patients and identified significantly reduced numbers of total NK cells and a striking shift in NK subsets, with a marked decrease in the CD56dim cell fraction compared to CD56bright cells, in both infections. This shift influenced the phenotype and functional capacity (gamma interferon production, killing) of the total NK pool. In addition, abnormalities in the functional capacity of the CD56dim NK subset were observed in HIV+ patients. The shared NK alterations were found to be associated with a significant reduction in serum levels of the innate cytokine interleukin 15 (IL-15). In vitro stimulation with IL-15 rescued NK cells of HIV+ and HCV+ patients from apoptosis and enhanced proliferation and functional activity. We hypothesize that the reduced levels of IL-15 present in the serum during HIV and HCV infections might impact NK cell homeostasis, contributing to the common alterations of the NK pool observed in these unrelated infections. 相似文献
16.
Loss of CD4+ T Cells in Human Immunodeficiency Virus Type 1-Infected Chimpanzees Is Associated with Increased Lymphocyte Apoptosis
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Supportive evidence that apoptosis contributes to loss of CD4+ lymphocytes in human immunodeficiency virus type 1 (HIV-1)-infected humans comes from an apparent lack of abnormal apoptosis in apathogenic lentivirus infections of nonhuman primates, including HIV-1 infection of chimpanzees. Two female chimpanzees were inoculated, one cervically and the other intravenously, with HIV-1 derived from the LAI/LAV-1b strain, which was isolated from a chimpanzee infected with the virus for 8 years. Within 6 weeks of infection, both recipient chimpanzees developed a progressive loss of CD4+ T cells which correlated with persistently high viral burdens and increased levels of CD4+ T-cell apoptosis both in vitro and in vivo. Lymph nodes from both animals also revealed evidence of immune hyperactivation. Intermediate levels of T-cell apoptosis in both peripheral blood and lymph nodes were seen in a third chimpanzee that had been infected with the LAI/LAV-1b strain for 9 years; this animal has maintained depressed CD4/CD8 T-cell ratios for the last 3 years. Similar analyses of cells from 4 uninfected animals and 10 other HIV-1-infected chimpanzees without loss of CD4+ cells revealed no difference in levels of apoptosis in these two control groups. These results demonstrate a correlation between immune hyperactivation, T-cell apoptosis, and chronic loss of CD4+ T cells in HIV-1-infected chimpanzees, providing additional evidence that apoptosis is an important factor in T-cell loss in AIDS. Furthermore, the results show that some HIV-1 strains are pathogenic for chimpanzees and that this species is not inherently resistant to HIV-1-induced disease. 相似文献
17.
M Grusdat D R McIlwain H C Xu V I Pozdeev J Knievel S Q Crome C Robert-Tissot R J Dress A A Pandyra D E Speiser E Lang S K Maney A R Elford S R Hamilton S Scheu K Pfeffer J Bode H-W Mittrücker M Lohoff M Huber D H?ussinger P S Ohashi T W Mak K S Lang P A Lang 《Cell death and differentiation》2014,21(7):1050-1060
18.
Vaccari M Mattapallil J Song K Tsai WP Hryniewicz A Venzon D Zanetti M Reimann KA Roederer M Franchini G 《Journal of virology》2008,82(19):9629-9638
Adaptive CD4+ and CD8+ T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4+ T-cell deficiency. Depletion of CD4+ cells was performed in the immunized macaques at the peak of SIV-specific CD4+ T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8+ T cells prior to challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine-induced CD8+ T cells demonstrated that SIV-specific CD8+ T cells generated under conditions of CD4+ T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8+ T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4+ T cells are critical for the generation of effective CD8+ T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4+ and CD8+ T-cell responses and protect against early depletion of CD4+ T cells postinfection. 相似文献
19.
Plasmacytoid dendritic cells (pDC) are essential innate immune system cells that are lost from the circulation in human immunodeficiency virus (HIV)–infected individuals associated with CD4+ T cell decline and disease progression. pDC depletion is thought to be caused by migration to tissues or cell death, although few studies have addressed this directly. We used precise methods of enumeration and in vivo labeling with 5-bromo-2′-deoxyuridine to track recently divided pDC in blood and tissue compartments of monkeys with acute pathogenic simian immunodeficiency virus (SIV) infection. We show that pDC are lost from blood and peripheral lymph nodes within 14 days of infection, despite a normal frequency of pDC in bone marrow. Paradoxically, pDC loss masked a highly dynamic response characterized by rapid pDC mobilization into blood and a 10- to 20-fold increase in recruitment to lymph nodes relative to uninfected animals. Within lymph nodes, pDC had increased levels of apoptosis and necrosis, were uniformly activated, and were infected at frequencies similar to CD4+ T cells. Nevertheless, remaining pDC had essentially normal functional responses to stimulation through Toll-like receptor 7, with half of lymph node pDC producing both TNF-α and IFN-α. These findings reveal that cell migration and death both contribute to pDC depletion in acute SIV infection. We propose that the rapid recruitment of pDC to inflamed lymph nodes in lentivirus infection has a pathologic consequence, bringing cells into close contact with virus, virus-infected cells, and pro-apoptotic factors leading to pDC death. 相似文献
20.
Yumi Nakayama Erin H. Plisch Jeremy Sullivan Chester Thomas Charles J. Czuprynski Bryan R. G. Williams M. Suresh 《PLoS pathogens》2010,6(6)
Type I interferons (IFNs) are known to mediate viral control, and also promote survival and expansion of virus-specific CD8+ T cells. However, it is unclear whether signaling cascades involved in eliciting these diverse cellular effects are also distinct. One of the best-characterized anti-viral signaling mechanisms of Type I IFNs is mediated by the IFN-inducible dsRNA activated protein kinase, PKR. Here, we have investigated the role of PKR and Type I IFNs in regulating viral clearance and CD8+ T cell response during primary and secondary viral infections. Our studies demonstrate differential requirement for PKR, in viral control versus elicitation of CD8+ T cell responses during primary infection of mice with lymphocytic choriomeningitis virus (LCMV). PKR-deficient mice mounted potent CD8+ T cell responses, but failed to effectively control LCMV. The compromised LCMV control in the absence of PKR was multifactorial, and linked to less effective CD8+ T cell-mediated viral suppression, enhanced viral replication in cells, and lower steady state expression levels of IFN-responsive genes. Moreover, we show that despite normal expansion of memory CD8+ T cells and differentiation into effectors during a secondary response, effective clearance of LCMV but not vaccinia virus required PKR activity in infected cells. In the absence of Type I IFN signaling, secondary effector CD8+ T cells were ineffective in controlling both LCMV and vaccinia virus replication in vivo. These findings provide insight into cellular pathways of Type I IFN actions, and highlight the under-appreciated importance of innate immune mechanisms of viral control during secondary infections, despite the accelerated responses of memory CD8+ T cells. Additionally, the results presented here have furthered our understanding of the immune correlates of anti-viral protective immunity, which have implications in the rational design of vaccines. 相似文献