scholarly journals Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

2015 ◽  
Vol 89 (7) ◽  
pp. 3542-3556 ◽  
Author(s):  
Timothée Bruel ◽  
Chiraz Hamimi ◽  
Nathalie Dereuddre-Bosquet ◽  
Antonio Cosma ◽  
So Youn Shin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Cell Responses ◽  
Cell Depletion ◽  
Viral Control ◽  
Cell Responses ◽  
Cynomolgus Macaques ◽  
Hiv 1

ABSTRACTThe spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8+T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8+T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8+T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8+T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8+T cells that lacked efficient SIV suppression capacityex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4+T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8+cell depletion and inducible SIV replication from its CD4+T cellsin vitro. Altogether, our results suggest that CD8+T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control.IMPORTANCESpontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8+T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8+T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8+cells induced a rise in the viral load. However, viremia was correlated with CD4+T-cell activation subsequent to CD8+cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8+T cells. Our results suggest that CD8+T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.

scholarly journals HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

2019 ◽  
Vol 16 (4) ◽  
pp. 302-314
Author(s):  
Chinnambedu Ravichandran Swathirajan ◽  
Ramachandran Vignesh ◽  
Greer Waldrop ◽  
Uma Shanmugasundaram ◽  
Pannerselvam Nandagopal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Activation Rates ◽  
Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

scholarly journals Subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques

2021 ◽  
Vol 17 (7) ◽  
pp. e1009668
Author(s):  
Takushi Nomura ◽  
Hiroyuki Yamamoto ◽  
Masako Nishizawa ◽  
Trang Thi Thu Hau ◽  
Shigeyoshi Harada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Post Infection ◽  
Clinical Manifestations ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Viral Rna ◽  
Viral Control ◽  
Cell Responses ◽  
Cynomolgus Macaques

SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10–17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.

scholarly journals CD8+T Cell Breadth andEx VivoVirus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

2016 ◽  
Vol 90 (15) ◽  
pp. 6818-6831 ◽  
Author(s):  
Catherine K. Koofhethile ◽  
Zaza M. Ndhlovu ◽  
Christina Thobakgale-Tshabalala ◽  
Julia G. Prado ◽  
Nasreen Ismail ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Hla Class I ◽  
Class I ◽  
Viral Control ◽  
Gag Protein ◽  
Cell Responses ◽  
Hiv 1

ABSTRACTThe mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P= 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8+T cell responses against Gag and enhanced ability of CD8+T cells to suppress viral replicationex vivo. In some cases, loss of virological control was associated with reduction in the total breadth of CD8+T cell responses in the absence of differences in HIV-1-specific CD8+T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8+T cell responses characterized by reduced ability to suppress viral replicationex vivo. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8+T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8+T cell-independent mechanisms.IMPORTANCEHost mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)-naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8+T cells that targeted the Gag protein, and CD8+T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8+T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine.

scholarly journals Subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques

2021 ◽  
Author(s):  
Takushi Nomura ◽  
Hiroyuki Yamamoto ◽  
Masako Nishizawa ◽  
Trang Hau ◽  
Shigeyoshi Harada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Post Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Viral Rna ◽  
Viral Control ◽  
Cell Responses ◽  
Cynomolgus Macaques

SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10-17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.

scholarly journals Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells

2016 ◽  
Vol 84 (9) ◽  
pp. 2627-2638 ◽  
Author(s):  
Charles S. Rosenberg ◽  
Weibo Zhang ◽  
Juan M. Bustamante ◽  
Rick L. Tarleton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Trypanosoma Cruzi ◽  
T Cell Responses ◽  
Content Type ◽  
Cell Responses ◽  
Pathogen Control ◽  
Immunodominant Epitopes

Trypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.

scholarly journals B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asuka Tanaka ◽  
Kentaro Ide ◽  
Yuka Tanaka ◽  
Masahiro Ohira ◽  
Hiroyuki Tahara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Transplant Recipients ◽  
Cell Responses ◽  
Anti Cd20

AbstractPretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.

scholarly journals High Frequencies of Functional Virus-Specific CD4+ T Cells in SARS-CoV-2 Subjects With Olfactory and Taste Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Dalila Mele ◽  
Anna Calastri ◽  
Eugenia Maiorano ◽  
Antonella Cerino ◽  
Michele Sachs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Control Group ◽  
Presenting Symptoms ◽  
Cell Responses ◽  
Taste Disorders ◽  
Specific Igg

Olfactory and taste disorders (OTD) are commonly found as presenting symptoms of SARS-CoV-2 infection in patients with clinically mild COVID-19. Virus-specific T cells are thought to play an important role in the clearance of SARS-CoV-2; therefore the study of T cell specific immune responses in patients with mild symptoms may help to understand their possible role in protection from severe disease. We evaluated SARS-CoV-2-specific T cell responses to four different peptide megapools covering all SARS-CoV-2 proteins during the acute phase of the disease in 33 individuals with mild or no other symptom beside OTD and in 22 age-matched patients with severe infection. A control group of 15 outpatients with OTD and consistently negative nasopharyngeal SARS-CoV-2 RNA swabs and virus-specific IgG serology was included in the study. Increased frequencies of virus-specific CD4+ and CD8+ T cells were found in SARS-CoV-2 positive patients with OTD compared with those with severe COVID-19 and with SARS-CoV-2 negative OTD individuals. Moreover, enhanced CD4+ and CD8+ T-cell activation induced by SARS-CoV-2 peptides was associated with higher interferon (IFN)γ production. Increased frequencies of Spike (S1/S2)-specific CD4+ T cells showing enhanced IFNγ secretion and granzyme B content were associated with serum spike-specific IgG in the OTD group. In conclusion, patients with SARS-CoV-2 induced OTD develop highly functional virus-specific CD4+ and CD8+ T cells during the symptomatic phase of the disease, suggesting that robust and coordinated T-cell responses provide protection against extension of COVID-19 to the lower respiratory tract.

Abstract 449: Novel Role of Bim in the Regulation of Allogeneic T-Cell Activation and Development of Transplant Vasculopathy

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Anna von Rossum ◽  
Winnie Enns ◽  
Yu P Shi ◽  
Jonathan C Choy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Intimal Thickening ◽  
Cell Responses ◽  
Transplant Vasculopathy

Transplant vasculopathy (TV) is an arteriosclerotic disease characterized by intimal thickening of allograft arteries and is a leading cause of heart transplant rejection. T cell responses towards allograft arteries are responsible for the development of TV and understanding the regulatory pathways controlling T cell activation in allograft arteries provides opportunities for the therapeutic attenuation of TV as well as other arteriosclerotic diseases. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses after viral infections by inducing cell death of effector T cells but its role in regulating allogeneic T cell responses is not known. We compared cell death and alloantigen-driven activation of T cells from Bim +/+ (wild-type), Bim +/- and Bim -/- mice as well as the development of TV in these mice. Bim was required for cell death of both CD4 and CD8 T cells in response to cytokine deprivation in vitro . Unexpectedly, Bim was also required for alloantigen-induced proliferation of both CD4 and CD8 T cells as well as for IL-2 production. When TV was examined in aortic interposition grafts implanted into complete major histocompatibility complex-mismatched mice, intimal thickening was significantly reduced in Bim +/- but not Bim -/- recipients as compared to Bim +/+ counterparts. There was signficantly less CD4 T cell accumulation in the intima of arteries from Bim +/- as compared to Bim +/+ recipients but this effect was not observed in Bim -/- recipients. The accumulation of CD8 T cells in allograft arteries was not affected by differences in Bim expression. Taken together, our data support a novel role for Bim in driving T cell activation in response to allogeneic stimuli and indicate that the effects of this Bcl-2 protein in the pathogenesis of TV likely depends on its dual role in supporting T cell activation and death.

scholarly journals DNA gag/Adenovirus Type 5 (Ad5) gag and Ad5 gag/Ad5 gag Vaccines Induce Distinct T-Cell Response Profiles

2008 ◽  
Vol 82 (16) ◽  
pp. 8161-8171 ◽  
Author(s):  
Kara S. Cox ◽  
James H. Clair ◽  
Michael T. Prokop ◽  
Kara J. Sykes ◽  
Sheri A. Dubey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Adenovirus Type ◽  
T Cell Response ◽  
Cell Responses ◽  
Response Profiles ◽  
Adenovirus Type 5 ◽  
Hiv 1

ABSTRACT Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (HIV-1)-specific T-cell responses. Here we present a comprehensive evaluation of the T-cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1β, and gamma interferon production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T-cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1-specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results for future vaccine development will be discussed.

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