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 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 Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

2022 ◽  
Author(s):  
Christine E. Nelson ◽  
Sivaranjani Namasivayam ◽  
Taylor W. Foreman ◽  
Keith D. Kauffman ◽  
Shunsuke Sakai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Post Infection ◽  
Rhesus Macaques ◽  
Myeloid Cells ◽  
T Cell Responses ◽  
Viral Rna ◽  
Viral Control ◽  
Cell Responses

SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. We used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated myeloid cells in the bronchoalveolar lavage (BAL) were found on days ~3-4. Virus-specific effector CD8 and CD4 T cells were detectable in the BAL and lung tissue on days ~7-10, after viral RNA, lung inflammation, and IFN-activated myeloid cells had declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

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 COVID-19 convalescents exhibit deficient humoral and T cell responses to variant of concern Spike antigens at 12 month post-infection

2021 ◽  
Author(s):  
Pablo Garcia-Valtanen ◽  
Christopher Martin Hope ◽  
Makutiro Ghislain Masavuli ◽  
Arthur Eng Lip Yeow ◽  
Harikrishnan Balachandran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Post Infection ◽  
T Cell Responses ◽  
Memory B Cells ◽  
Pseudotyped Virus ◽  
Cell Responses ◽  
Specific Memory ◽  
Cell Functionality

Background The duration and magnitude of SARS-CoV-2 immunity after infection, especially with regard to the emergence of new variants of concern (VoC), remains unclear. Here, immune memory to primary infection and immunity to VoC was assessed in mild-COVID-19 convalescents one year after infection and in the absence of viral re-exposure or COVID-19 vaccination. Methods Serum and PBMC were collected from mild-COVID-19 convalescents at ~6 and 12 months after a COVID-19 positive PCR (n=43) and from healthy SARS-CoV-2-seronegative controls (n=15-40). Serum titers of RBD and Spike-specific Ig were quantified by ELISA. Virus neutralisation was assessed against homologous, pseudotyped virus and homologous and VoC live viruses. Frequencies of Spike and RBD-specific memory B cells were quantified by flow cytometry. Magnitude of memory T cell responses was quantified and phenotyped by activation-induced marker assay, while T cell functionality was assessed by intracellular cytokine staining using peptides specific to homologous Spike virus antigen and four VoC Spike antigens. Findings At 12 months after mild-COVID-19, >90% of convalescents remained seropositive for RBD-IgG and 88.9% had circulating RBD-specific memory B cells. Despite this, only 51.2% convalescents had serum neutralising activity against homologous live-SARS-CoV-2 virus, which decreased to 44.2% when tested against live B.1.1.7, 4.6% against B.1.351, 11.6% against P.1 and 16.2%, against B.1.617.2 VoC. Spike and non-Spike-specific T cells were detected in >50% of convalescents with frequency values higher for Spike antigen (95% CI, 0.29-0.68% in CD4+ and 0.11-0.35% in CD8+ T cells), compared to non-Spike antigens. Despite the high prevalence and maintenance of Spike-specific T cells in Spike 'high-responder' convalescents at 12 months, T cell functionality, measured by cytokine expression after stimulation with Spike epitopes corresponding to VoC was severely affected. Interpretations SARS-CoV-2 immunity is retained in a significant proportion of mild COVID-19 convalescents 12 months post-infection in the absence of re-exposure to the virus. Despite this, changes in the amino acid sequence of the Spike antigen that are present in current VoC result in virus evasion of neutralising antibodies, as well as evasion of functional T cell responses.

scholarly journals HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4+T Cell Responses

2015 ◽  
Vol 90 (5) ◽  
pp. 2208-2220 ◽  
Author(s):  
Srinika Ranasinghe ◽  
Damien Z. Soghoian ◽  
Madelene Lindqvist ◽  
Musie Ghebremichael ◽  
Faith Donaghey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Hiv Infection ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Antibody Activity ◽  
Cell Responses

ABSTRACTAntigen-specific CD4+T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4+T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4+T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4+T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4+T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4+T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4+T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4+T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4+T cells and, to a lesser extent, gp41-specific CD4+T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.IMPORTANCEOne of the earliest discoveries related to CD4+T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4+T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4+T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4+T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4+T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4+T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.

scholarly journals Virus-Specific CD4+ and CD8+ Cytotoxic T-Cell Responses and Long-Term T-Cell Memory in Individuals Vaccinated against Polio

2005 ◽  
Vol 79 (10) ◽  
pp. 5988-5995 ◽  
Author(s):  
Rahnuma Wahid ◽  
Martin J. Cannon ◽  
Marie Chow
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses

ABSTRACT The presence of poliovirus (PV)-specific CD4+ T cells in individuals vaccinated against polio has been shown, but CD8+ T-cell responses have not been described. Here, we functionally characterize the CD4+ T-cell response and show for the first time that dendritic cells and macrophages can stimulate PV-specific CD8+ T-cell responses in vitro from vaccinees. Both CD4+ T and CD8+ T cells secrete gamma interferon in response to PV antigens and are cytotoxic via the perforin/granzyme B-mediated pathway. Furthermore, the T cells also recognize and kill Sabin 1 vaccine-infected targets. The macrophage-stimulated CD4+ T and CD8+ T cells most likely represent memory T cells that persist for long periods in vaccinated individuals. Thus, immunity to PV vaccination involves not only an effective neutralizing antibody titer but also long-term CD4+ and CD8+ cytotoxic T-cell responses.

scholarly journals Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infection

2008 ◽  
Vol 205 (3) ◽  
pp. 543-555 ◽  
Author(s):  
Sang-Jun Ha ◽  
Scott N. Mueller ◽  
E. John Wherry ◽  
Daniel L. Barber ◽  
Rachael D. Aubert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treatment Strategies ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Therapeutic Vaccination ◽  
Chronic Infections ◽  
Viral Control ◽  
Cell Responses ◽  
Cell Immunity

Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.

scholarly journals Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination

2021 ◽  
Author(s):  
Mark M. Painter ◽  
Divij Mathew ◽  
Rishi R. Goel ◽  
Sokratis A. Apostolidis ◽  
Ajinkya Pattekar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Infection ◽  
Vaccine Dose ◽  
Booster Vaccination ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Integrated Analysis ◽  
Cell Responses ◽  
Rapid Induction

SummaryThe SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+ T cell responses in all subjects after the first vaccine dose. CD8+ T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+ T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+ and CD8+ T cell responses in SARS-CoV-2 naïve subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+ T cells.Graphical Abstract

scholarly journals Conditional silencing of H-2Dbclass I molecule expression on dendritic cells modulates the protective and pathogenic kinetics of virus-antigen specific CD8 T cell responses during Theiler’s Virus infection

2019 ◽  
Author(s):  
Zachariah P. Tritz ◽  
Robin C. Orozco ◽  
Courtney S. Malo ◽  
Lila T Yokanovich ◽  
Katayoun Ayasoufi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Class I ◽  
Viral Control ◽  
Cell Responses

ABSTRACTTheiler’s murine encephalomyelitis virus (TMEV) infection of the central nervous system is rapidly cleared in C57BL/6 mice by an anti-viral CD8 T cell response restricted by the MHC class I molecule, H-2Db. While the CD8 T cell response against neurotropic viruses is well characterized, the identity and function of the antigen presenting cell(s) involved in this process is(are) less well defined. To address this gap in knowledge, we developed a novel C57BL/6 H-2Dbconditional knockout mouse that expresses an H-2Dbtransgene in which the transmembrane domain locus is flanked by LoxP sites. We crossed these H-2DbLoxP mice with MHC class I-deficient mice expressing Cre-recombinase under either the CD11c or LysM promoter in order to silence H-2Dbrestricted antigen presentation predominantly in dendritic cells or macrophages, respectively. Upon challenge with intracranial TMEV infection, we observe that CD11c+ APCs are critical for early priming of CD8 T cells against the immunodominant TMEV peptide VP2121-130 presented in the context of the H-2Dbmolecule. This stands in stark contrast to later time points post TMEV infection where CD11c+ APCs appear dispensable for the activation of antigen-specific T cells; the functionality of these late-arising antiviral CD8 T cells is reflected in the restoration of viral control at later time points. These late-arising CD8 T cells also retain their capacity to induce blood-brain barrier disruption. In contrast, when H-2Dbrestricted antigen presentation was selectively silenced in LysM+ APCs there was no overt impact on the priming of Db:VP2121-130 epitope-specific CD8 T cells, although a modest reduction in immune cell entry into the CNS was observed. This work establishes a model system which enables critical dissection of MHC class I restricted antigen presentation to T cells, revealing cell specific and temporal features involved in the generation of antiviral CD8 T cell responses. Employing this novel system, we established CD11c+ cells as a pivotal driver of acute, but not later-arising, antiviral CD8 T cell responses against the TMEV immunodominant epitope VP2121-130, with functional implications both for T cell-mediated viral control and immunopathology.

scholarly journals Immunotherapeutic effects of IL-7 during a chronic viral infection in mice

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5123-5132 ◽  
Author(s):  
Som G. Nanjappa ◽  
Eui Ho Kim ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
T Cell Responses ◽  
Duration Of Treatment ◽  
Viral Control ◽  
Cell Responses ◽  
Chronic Viral Infections

AbstractViral persistence during chronic viral infections is associated with a progressive loss of T-cell effector function called functional exhaustion. There is therefore a need to develop immunotherapies to remediate the functional deficits of T cells during these infections. We investigated the immunotherapeutic effects of IL-7 during chronic lymphocytic choriomeningitis virus infection in mice. Our results showed that the effects of IL-7 on T cells depend on the viral load, timing, and duration of treatment during the course of the infection. We document that the effectiveness of IL-7 was constrained by high viral load early in the infection, but treatment for at least 3 weeks during declining viral titers mitigated the programmed contraction of CD8 T cells, markedly enhanced the number of high-quality polyfunctional virus-specific CD8 T cells with a nonexhausted phenotype, and accelerated viral control. Mechanistically, the enhancement of CD8 T-cell responses by IL-7 was associated with increased proliferation and induction of Bcl-2, but not with altered levels of PD-1 or Cbl-b. In summary, our results strongly suggest that IL-7 therapy is a potential strategy to bolster the quality and quantity of T-cell responses in patients with chronic viral infections.

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