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1.
Alter G Rihn S Streeck H Teigen N Piechocka-Trocha A Moss K Cohen K Meier A Pereyra F Walker B Altfeld M 《Journal of virology》2008,82(19):9668-9677
Virus-specific CD8+ T cells play a central role in the control of viral infections, including human immunodeficiency virus type 1 (HIV-1) infection. However, despite the presence of strong and broad HIV-specific CD8+ T-cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions and fail to clear the infection. Mounting evidence suggests that the upregulation of several inhibitory regulatory receptors on the surface of CD8+ T cells during HIV-1 infection may contribute directly to the impairment of T-cell function. Here, we investigated the role of killer immunoglobulin receptors (KIR), which are expressed on NK cells and on CD8+ T cells, in regulating CD8+ T-cell function in HIV-1 infection. KIR expression was progressively upregulated on CD8+ T cells during HIV-1 infection and correlated with the level of viral replication. Expression of KIR was associated with a profound inhibition of cytokine secretion, degranulation, proliferation, and activation by CD8+ T cells following stimulation with T-cell receptor (TCR)-dependent stimuli. In contrast, KIR+ CD8+ T cells responded potently to TCR-independent stimulation, demonstrating that these cells are functionally competent. KIR-associated suppression of CD8+ T-cell function was independent of ligand engagement, suggesting that these regulatory receptors may constitutively repress TCR activation. This ligand-independent repression of TCR activation of KIR+ CD8+ T cells may represent a significant barrier to therapeutic interventions aimed at improving the quality of the HIV-specific CD8+ T-cell response in infected individuals. 相似文献
2.
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
3.
Role of human immunodeficiency virus (HIV)-specific T-cell immunity in control of dual HIV-1 and HIV-2 infection 总被引:2,自引:0,他引:2
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Zheng NN McElrath MJ Sow PS Hawes SE Diallo-Agne H Stern JE Li F Mesher AL Robinson AD Gottlieb GS Huang Y Kiviat NB 《Journal of virology》2007,81(17):9061-9071
Progressive immune dysfunction and AIDS develop in most cases of human immunodeficiency virus type 1 (HIV-1) infection but in only 25 to 30% of persons with HIV-2 infection. However, the natural history and immunologic responses of individuals with dual HIV-1 and HIV-2 infection are largely undefined. Based on our previous findings, we hypothesized that among patients with dual infection the control of HIV-1 is associated with the ability to respond to HIV-2 Gag epitopes and to maintain HIV-specific CD4+ T-cell responses. To test this, we compared the HIV-specific ex vivo IFN-γ enzyme-linked immunospot (ELISPOT) assay responses of 19 dually infected individuals to those of persons infected with HIV-1 or HIV-2 only. Further, we assessed the functional profile of HIV Gag-specific CD4+ and CD8+ T cells from nine HIV dually infected patients by using a multicolor intracellular cytokine staining assay. As determined by ELISPOT assay, the magnitude and frequency of IFN-γ-secreting T-cell responses to gene products of HIV-1 were higher than those to gene products of HIV-2 (2.64 versus 1.53 log10 IFN-γ spot-forming cells/106 cells [90% versus 63%, respectively].) Further, HIV-1 Env-, Gag-, and Nef- and HIV-2 Gag-specific responses were common; HIV-2 Nef-specific responses were rare. HIV-specific CD4+ T helper responses were detected in nine of nine dually infected subjects, with the majority of these T cells producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) and, to a lesser extent, interleukin-2. The HIV-1 plasma viral load was inversely correlated with HIV-2 Gag-specific IFN-γ-/TNF-α-secreting CD4+ and HIV-2 Gag-specific IFN-γ-secreting CD8+ T cells. In conclusion, the T-cell memory responses associated with containment of single HIV-1 and HIV-2 infection play a similar significant role in the immune control of dual HIV-1 and HIV-2 infection. 相似文献
4.
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
5.
Caroline Boda Bertrand Courtioux Pierre Roques Lynda Pervieux Gédéon Vatunga Théophile Josenando Constant Roger Ayenengoye Bernard Bouteille Marie-Odile Jauberteau Sylvie Bisser 《PloS one》2009,4(7)
Human African trypanosomiasis (HAT) is a deadly vector-born disease caused by an extracellular parasite, the trypanosome. Little is known about the cellular immune responses elicited by this parasite in humans. We used multiparameter flow cytometry to characterize leukocyte immunophenotypes in the blood and cerebrospinal fluid (CSF) of 33 HAT patients and 27 healthy controls identified during a screening campaign in Angola and Gabon. We evaluated the subsets and activation markers of B and T lymphocytes. Patients had a higher percentage of CD19+ B lymphocytes and activated B lymphocytes in the blood than did controls, but lacked activated CD4+ T lymphocytes (CD25+). Patients displayed no increase in the percentage of activated CD8+ T cells (HLA-DR+, CD69+ or CD25+), but memory CD8 T-cell levels (CD8+CD45RA−) were significantly lower in patients than in controls, as were effector CD8 T-cell levels (CD8+CD45RA+CD62L−). No relationship was found between these blood immunophenotypes and disease severity (stage 1 vs 2). However, CD19+ B-cell levels in the CSF increased with disease severity. The patterns of T and B cell activation in HAT patients suggest that immunomodulatory mechanisms may operate during infection. Determinations of CD19+ B-cell levels in the CSF could improve disease staging. 相似文献
6.
Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels 总被引:2,自引:1,他引:1
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Sanchez A Lukwiya M Bausch D Mahanty S Sanchez AJ Wagoner KD Rollin PE 《Journal of virology》2004,78(19):10370-10377
Peripheral blood samples obtained from patients during an outbreak of Ebola virus (Sudan species) disease in Uganda in 2000 were used to phenotype peripheral blood mononuclear cells (PBMC), quantitate gene expression, measure antigenemia, and determine nitric oxide levels. It was determined that as the severity of disease increased in infected patients, there was a corresponding increase in antigenemia and leukopenia. Blood smears revealed thrombocytopenia, a left shift in neutrophils (in some cases degenerating), and atypical lymphocytes. Infected patients who died had reduced numbers of T cells, CD8+ T cells, and activated (HLA-DR+) CD8+ T cells, while the opposite was noted for patients who survived the disease. Expression levels of cytokines, Fas antigen, and Fas ligand (TaqMan quantitation) in PBMC from infected patients were not significantly different from those in uninfected patients (treated in the same isolation wards), nor was there a significant increase in expression compared to healthy volunteers (United States). This unresponsive state of PBMC from infected patients despite high levels of circulating antigen and virus replication suggests that some form of immunosuppression had developed. Ebola virus RNA levels (virus load) in PBMC specimens were found to be much higher in infected patients who died than patients who survived the disease. Similarly, blood levels of nitric oxide were much higher in fatal cases (increasing with disease severity), and extremely elevated levels (≥150 μM) would have negatively affected vascular tone and contributed to virus-induced shock. 相似文献
7.
Matthew D. H. Lay Janka Petravic Shari N. Gordon Jessica Engram Guido Silvestri Miles P. Davenport 《Journal of virology》2009,83(15):7517-7523
The acute phases of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection are characterized by rapid and profound depletion of CD4+ T cells from the guts of infected individuals. The large number of CD4+ T cells in the gut (a large fraction of which are activated and express the HIV/SIV coreceptor CCR5), the high level of infection of these cells, and the temporal coincidence of this CD4+ T-cell depletion with the peak of virus in plasma in acute infection suggest that the intestinal mucosa may be the major source of virus driving the peak viral load. Here, we used data on CD4+ T-cell proportions in the lamina propria of the rectums of SIV-infected rhesus macaques (which progress to AIDS) and sooty mangabeys (which do not progress) to show that in both species, the depletion of CD4+ T cells from this mucosal site and its maximum loss rate are often observed several days before the peak in viral load, with few CD4+ T cells remaining in the rectum by the time of peak viral load. In contrast, the maximum loss rate of CD4+ T cells from bronchoalveolar lavage specimens and lymph nodes coincides with the peak in virus. Analysis of the kinetics of depletion suggests that, in both rhesus macaques and sooty mangabeys, CD4+ T cells in the intestinal mucosa are a highly susceptible population for infection but not a major source of plasma virus in acute SIV infection.The acute phase of human immunodeficiency virus (HIV) infection is characterized by moderate CD4+ T-cell depletion in blood, followed by a transient partial restoration of CD4+ T-cell numbers and eventually by a slow long-term CD4+ T-cell decline in the chronic phase that lasts for several years. Studies of CD4+ T-cell depletion in mucosal sites, often conducted with simian immunodeficiency virus (SIV)-infected macaques, have demonstrated that mucosal CD4+ T-cell depletion is more rapid and profound (3, 10, 13, 19, 21). The severe depletion of cells in the gut in early infection is thought to be driven in part by the phenotype of the cells present, which are predominantly CCR5+ and in general more activated than their circulating counterparts. As such, these mucosal CD4+ T cells are highly susceptible to productive infection with the dominant CCR5-tropic strains of HIV and SIV present in early infection (20). The rapid depletion of CD4+ T cells at mucosal sites is accompanied by relatively high numbers of infected cells (10, 13) and is temporally associated with the peak viral load in plasma, suggesting that the infection of mucosal CD4+ T cells may be responsible for the majority of virus replication occurring during acute infection (10, 15, 21, 22).The size of the CD4+ T-cell pool in the gut is a matter of some controversy, with estimates ranging from ∼5 to 50% of the total body pool of these cells (reviewed in reference 5). Regardless of the precise numbers, the gut (and particularly the mucosal lamina propria) contains a significant proportion of the body CD4+ CCR5+ memory T cells, which are depleted very early in infection. However, whether CD4+ T cells in the gut are merely a target of early infection or whether they are a major driver of early viral growth and peak viral loads in acute infection is unclear. Here we use a combination of experimental data and modeling to demonstrate that the gut is unlikely to be a major source of virus production in acute SIV infection. 相似文献
8.
Allogeneic differences in the dependence on CD4+ T-cell help for virus-specific CD8+ T-cell differentiation
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CD4+ T-cell help enables antiviral CD8+ T cells to differentiate into fully competent memory cells and sustains CD8+ T-cell-mediated immunity during persistent virus infection. We recently reported that mice of C57BL/6 and C3H strains differ in their dependence on CD28 and CD40L costimulation for long-term control of infection by polyoma virus, a persistent mouse pathogen. In this study, we asked whether mice of these inbred strains also vary in their requirement for CD4+ T-cell help for generating and maintaining polyoma virus-specific CD8+ T cells. CD4+ T-cell-depleted C57BL/6 mice mounted a robust antiviral CD8+ T-cell response during acute infection, whereas unhelped CD8+ T-cell effectors in C3H mice were functionally impaired during acute infection and failed to expand upon antigenic challenge during persistent infection. Using (C57BL/6 × C3H)F1 mice, we found that the dispensability for CD4+ T-cell help for the H-2b-restricted polyoma virus-specific CD8+ T-cell response during acute infection extends to the H-2k-restricted antiviral CD8+ T cells. Our findings demonstrate that dependence on CD4+ T-cell help for antiviral CD8+ T-cell effector differentiation can vary among allogeneic strains of inbred mice. 相似文献
9.
Robertson SJ Ammann CG Messer RJ Carmody AB Myers L Dittmer U Nair S Gerlach N Evans LH Cafruny WA Hasenkrug KJ 《Journal of virology》2008,82(1):408-418
Friend virus (FV) and lactate dehydrogenase-elevating virus (LDV) are endemic mouse viruses that can cause long-term chronic infections in mice. We found that numerous mouse-passaged FV isolates also contained LDV and that coinfection with LDV delayed FV-specific CD8+ T-cell responses during acute infection. While LDV did not alter the type of acute pathology induced by FV, which was severe splenomegaly caused by erythroproliferation, the immunosuppression mediated by LDV increased both the severity and the duration of FV infection. Compared to mice infected with FV alone, those coinfected with both FV and LDV had delayed CD8+ T-cell responses, as measured by FV-specific tetramers. This delayed response accounted for the prolonged and exacerbated acute phase of FV infection. Suppression of FV-specific CD8+ T-cell responses occurred not only in mice infected concomitantly with LDV but also in mice chronically infected with LDV 8 weeks prior to infection with FV. The LDV-induced suppression was not mediated by T regulatory cells, and no inhibition of the CD4+ T-cell or antibody responses was observed. Considering that most human adults are carriers of chronically infectious viruses at the time of new virus insults and that coinfections with viruses such as human immunodeficiency virus and hepatitis C virus are currently epidemic, it is of great interest to determine how infection with one virus may impact host responses to a second infection. Coinfection of mice with LDV and FV provides a well-defined, natural host model for such studies. 相似文献
10.
High levels of viral replication contrast with only transient changes in CD4(+) and CD8(+) cell numbers during the early phase of experimental infection with simian immunodeficiency virus SIVmnd-1 in Mandrillus sphinx
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Onanga R Kornfeld C Pandrea I Estaquier J Souquière S Rouquet P Mavoungou VP Bourry O M'Boup S Barré-Sinoussi F Simon F Apetrei C Roques P Müller-Trutwin MC 《Journal of virology》2002,76(20):10256-10263
Early events during human immunodeficiency virus infections are considered to reflect the capacity of the host to control infection. We have studied early virus and host parameters during the early phase of simian immunodeficiency virus SIVmnd-1 nonpathogenic infection in its natural host, Mandrillus sphinx. Four mandrills were experimentally infected with a primary SIVmnd-1 strain derived from a naturally infected mandrill. Two noninfected control animals were monitored in parallel. Blood and lymph nodes were collected at three time points before infection, twice a week during the first month, and at days 60, 180, and 360 postinfection (p.i.). Anti-SIVmnd-1 antibodies were detected starting from days 28 to 32 p.i. Neither elevated temperature nor increased lymph node size were observed. The viral load in plasma peaked between days 7 to 10 p.i. (2 × 106 to 2 × 108 RNA equivalents/ml). Viremia then decreased 10- to 1,000-fold, reaching the viral set point between days 30 to 60 p.i. The levels during the chronic phase of infection were similar to that in the naturally infected donor mandrill (2 × 105 RNA equivalents/ml). The CD4+ cell numbers and percentages in blood and lymph nodes decreased slightly (<10%) during primary infection, and CD8+ cell numbers increased transiently. All values returned to preinfection infection levels by day 30 p.i. CD8+ cell numbers or percentages, in peripheral blood and lymph nodes, did not increase during the 1 year of follow-up. In conclusion, SIVmnd-1 has the capacity for rapid and extensive replication in mandrills. Despite high levels of viremia, CD4+ and CD8+ cell numbers remained stable in the post-acute phase of infection, raising questions regarding the susceptibility of mandrill T cells to activation and/or cell death in response to SIVmnd-1 infection in vivo. 相似文献
11.
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
12.
Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy
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Rosemarie D. Mason Sheilajen Alcantara Viv Peut Liyen Loh Jeffrey D. Lifson Robert De Rose Stephen J. Kent 《Journal of virology》2009,83(3):1501-1510
Practical immunotherapies for human immunodeficiency virus infection are needed. We evaluated inactivated simian immunodeficiency virus (SIV) pulsed onto fresh peripheral blood mononuclear cells in 12 pigtail macaques with chronic SIVmac251 infection for T-cell immunogenicity in a randomized cross-over design study. The immunotherapy was safe and convincingly induced high levels of SIV-specific CD4+ T-cell responses (mean, 5.9% ± 1.3% of all CD4+ T cells) and to a lesser extent SIV-specific CD8+ T-cell responses (mean, 0.7% ± 0.4%). Responses were primarily directed toward Gag and less frequently toward Env but not Pol or regulatory/accessory SIV proteins. T-cell responses against Gag were generally broad and polyfunctional, with a mean of 2.7 CD4+ T-cell epitopes mapped per animal and more than half of the SIV Gag-specific CD4+ T cells expressing three or more effector molecules. The immunogenicity was comparable to that found in previous studies of peptide-pulsed blood cells. Despite the high-level immunogenicity, no reduction in viral load was observed in the chronically viremic macaques. This contrasts with our studies of immunization with peptide-pulsed blood cells during early SIV infection in macaques. Future studies of inactivated virus-pulsed blood cell immunotherapy during early infection of patients receiving antiretroviral therapy are warranted. 相似文献
13.
Antigen-Specific Expansion of Cytotoxic T Lymphocytes in Acute Measles Virus Infection 总被引:6,自引:3,他引:3
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Juthathip Mongkolsapaya Assan Jaye Margaret F. C. Callan Albert F. Magnusen Andrew J. McMichael Hilton C. Whittle 《Journal of virology》1999,73(1):67-71
Skewing of the T-cell receptor repertoire of CD8+ T cells has been shown in some persistent infections with viruses, such as human immunodeficiency virus, simian immunodeficiency virus, and Epstein-Barr virus. We have demonstrated that similar distortions also occur in nonpersistent measles virus infection. In addition, two of four children immunized with live, attenuated measles virus showed larger and more persistent CD8+ T-cell expansions than their naturally infected counterparts. The expanded lymphocyte populations were monoclonal or oligoclonal and lysed target cells infected with recombinant vaccinia virus expressing measles virus protein. These results demonstrate that the expansions of CD8+ T lymphocytes are antigen driven. 相似文献
14.
Clearance of an Influenza A Virus by CD4+ T Cells Is Inefficient in the Absence of B Cells
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The primary CD8+ T-cell response protected most B-cell-deficient μMT mice against intranasal infection with the HKx31 influenza A virus. Prior exposure did not prevent reinfection upon homologous challenge, and the recall CD8+ T-cell response cleared the virus from the lung within 7 days. Depleting the CD8+ T cells substantially reduced the capacity of these primed mice to deal with the infection, in spite of evidence for established CD4+ T-cell memory. Thus, the control of this relatively mild influenza virus by both primary and secondary CD4+ T-cell responses is relatively inefficient in the absence of B cells and CD8+ T cells. 相似文献
15.
Dendritic cells are less susceptible to human immunodeficiency virus type 2 (HIV-2) infection than to HIV-1 infection 总被引:1,自引:0,他引:1
Duvall MG Loré K Blaak H Ambrozak DA Adams WC Santos K Geldmacher C Mascola JR McMichael AJ Jaye A Whittle HC Rowland-Jones SL Koup RA 《Journal of virology》2007,81(24):13486-13498
Human immunodeficiency virus type 1 (HIV-1) infection of dendritic cells (DCs) has been documented in vivo and may be an important contributor to HIV-1 transmission and pathogenesis. HIV-1-specific CD4+ T cells respond to HIV antigens presented by HIV-1-infected DCs and in this process become infected, thereby providing a mechanism through which HIV-1-specific CD4+ T cells could become preferentially infected in vivo. HIV-2 disease is attenuated with respect to HIV-1 disease, and host immune responses are thought to be contributory. Here we investigated the susceptibility of primary myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to infection by HIV-2. We found that neither CCR5-tropic primary HIV-2 isolates nor a lab-adapted CXCR4-tropic HIV-2 strain could efficiently infect mDCs or pDCs, though these viruses could infect primary CD4+ T cells in vitro. HIV-2-exposed mDCs were also incapable of transferring virus to autologous CD4+ T cells. Despite this, we found that HIV-2-specific CD4+ T cells contained more viral DNA than memory CD4+ T cells of other specificities in vivo. These data suggest that either infection of DCs is not an important contributor to infection of HIV-2-specific CD4+ T cells in vivo or that infection of DCs by HIV-2 occurs at a level that is undetectable in vitro. The frequent carriage of HIV-2 DNA within HIV-2-specific CD4+ T cells, however, does not appear to be incompatible with preserved numbers and functionality of HIV-2-specific CD4+ T cells in vivo, suggesting that additional mechanisms contribute to maintenance of HIV-2-specific CD4+ T-cell help in vivo. 相似文献
16.
Dow C Oseroff C Peters B Nance-Sotelo C Sidney J Buchmeier M Sette A Mothé BR 《Journal of virology》2008,82(23):11734-11741
Activation of CD4+ T cells helps establish and sustain other immune responses. We have previously shown that responses against a broad set of nine CD4+ T-cell epitopes were present in the setting of lymphocytic choriomeningitis virus (LCMV) Armstrong infection in the context of H-2d. This is quite disparate to the H-2b setting, where only two epitopes have been identified. We were interested in determining whether a broad set of responses was unique to H-2d or whether additional CD4+ T-cell epitopes could be identified in the setting of the H-2b background. To pursue this question, we infected C57BL/6 mice with LCMV Armstrong and determined the repertoire of CD4+ T-cell responses using overlapping 15-mer peptides corresponding to the LCMV Armstrong sequence. We confirmed positive responses by intracellular cytokine staining and major histocompatibility complex (MHC)-peptide binding assays. A broad repertoire of responses was identified, consisting of six epitopes. These epitopes originate from the nucleoprotein (NP) and glycoprotein (GP). Out of the six newly identified CD4+ epitopes, four of them also stimulate CD8+ T cells in a statistically significant manner. Furthermore, we assessed these CD4+ T-cell responses during the memory phase of LCMV Armstrong infection and after infection with a chronic strain of LCMV and determined that a subset of the responses could be detected under these different conditions. This is the first example of a broad repertoire of shared epitopes between CD4+ and CD8+ T cells in the context of viral infection. These findings demonstrate that immunodominance is a complex phenomenon in the context of helper responses. 相似文献
17.
Critical Role for CD4+ T Cells in Controlling Retrovirus Replication and Spread in Persistently Infected Mice
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Reactivations of persistent viral infections pose a significant medical problem in immunocompromised cancer, transplant, and AIDS patients, yet little is known about how persistent viral infections are immunologically controlled. Here we describe a mouse model for investigating the role of the immune response in controlling a persistent retroviral infection. We demonstrate that, following recovery from acute Friend virus infection, a small number of B cells evade immunological destruction and harbor persistent virus. In vivo depletions of T-cell subsets in persistently infected mice revealed a critical role for CD4+ T cells in controlling virus replication, spread to the erythroid lineage, and induction of erythroleukemia. The CD4+ T-cell effect was independent of CD8+ T cells and in some cases was also independent of virus-neutralizing antibody responses. Thus, the CD4+ T cells may have had a direct antiviral effect. These results may have relevance for human immunodeficiency virus (HIV) infections where loss of CD4+ T cells is associated with an increase in HIV replication, reactivation of persistent viruses, and a high incidence of virus-associated cancers. 相似文献
18.
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
19.
CD4+ CCR5+ T-cell dynamics during simian immunodeficiency virus infection of Chinese rhesus macaques
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Monceaux V Viollet L Petit F Cumont MC Kaufmann GR Aubertin AM Hurtrel B Silvestri G Estaquier J 《Journal of virology》2007,81(24):13865-13875
Simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) provides a reliable model to study the relationship between lentivirus replication, cellular immune responses, and CD4+ T-cell dynamics. Here we investigated, using SIVmac251-infected RMs of a Chinese genetic background (which experience a slower disease progression than Indian RMs), the dynamics of CD4+ CCR5+ T cells, as this subset of memory/activated CD4+ T cells is both a preferential target of virus replication and a marker of immune activation. As expected, we observed that the number of circulating CD4+ CCR5+ T cells decreases transiently at the time of peak viremia. However, at 60 days postinfection, i.e., when set-point viremia is established, the level of CD4+ CCR5+ T cells was increased compared to the baseline level. Interestingly, this increase correlated with faster disease progression, higher plasma viremia, and early loss of CD4+ T-cell function, as measured by CD4+ T-cell count, the fraction of memory CD4+ T cells, and the recall response to purified protein derivative. Taken together, these data show a key difference between the dynamics of the CD4+ CCR5+ T-cell pool (and its relationship with disease progression) in Chinese RMs and those described in previous reports for Indian SIVmac251-infected RMs. As the SIV-associated changes in the CD4+ CCR5+ T-cell pool reflect the opposing forces of SIV replication (which reduces this cellular pool) and immune activation (which increases it), our data suggest that in SIV-infected Chinese RMs the impact of immune activation is more prominent than that of virus replication in determining the size of the pool of CD4+ CCR5+ T cells in the periphery. As progression of HIV infection in humans also is associated with a relative expansion of the level of CD4+ CCR5+ T cells, we propose that SIV infection of Chinese RMs is a very valuable and important animal model for understanding the pathogenesis of human immunodeficiency virus infection. 相似文献
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Lilian Lacerda Bueno Cristiane Guimar?es Morais Fernanda Fortes Araújo Juliana Assis Silva Gomes Rodrigo Corrêa-Oliveira Irene Silva Soares Marcus Vinícius Lacerda Ricardo Toshio Fujiwara érika Martins Braga 《PloS one》2010,5(3)
Circulation CD4+CD25+FoxP3+ regulatory T cells (Tregs) have been associated with the delicate balancing between control of overwhelming acute malaria infection and prevention of immune pathology due to disproportionate inflammatory responses to erythrocytic stage of the parasite. While the role of Tregs has been well-documented in murine models and P. falciparum infection, the phenotype and function of Tregs in P. vivax infection is still poorly characterized. In the current study, we demonstrated that patients with acute P. vivax infection presented a significant augmentation of circulating Tregs producing anti-inflammatory (IL-10 and TGF-β) as well as pro-inflammatory (IFN-γ, IL-17) cytokines, which was further positively correlated with parasite burden. Surface expression of GITR molecule and intracellular expression of CTLA-4 were significantly upregulated in Tregs from infected donors, presenting also a positive association between either absolute numbers of CD4+CD25+FoxP3+GITR+ or CD4+CD25+FoxP3+CTLA-4+ and parasite load. Finally, we demonstrate a suppressive effect of Treg cells in specific T cell proliferative responses of P. vivax infected subjects after antigen stimulation with Pv-AMA-1. Our findings indicate that malaria vivax infection lead to an increased number of activated Treg cells that are highly associated with parasite load, which probably exert an important contribution to the modulation of immune responses during P. vivax infection. 相似文献