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2.
Sci Immunol ; 7(70): eabf9393, 2022 Apr 08.
Article in English | MEDLINE | ID: covidwho-1784764

ABSTRACT

The ability of the adaptive immune system to form memory is key to providing protection against secondary infections. Resident memory T cells (TRM) are specialized T cell populations that reside within tissue sites where they await reencounter with their cognate antigen. TRM are distinct from circulating memory cells, including central and effector memory T cells, both functionally and transcriptionally. Since the discovery of TRM, most research has focused on CD8+ TRM, despite that CD4+ TRM are also abundant in most tissues. In the past few years, more evidence has emerged that CD4+ TRM can contribute both protective and pathogenic roles in disease. A complexity inherent to the CD4+ TRM field is the ability of CD4+ T cells to polarize into a multitude of distinct subsets and recognize not only viruses and intracellular bacteria but also extracellular bacteria, fungi, and parasites. In this review, we outline the key features of CD4+ TRM in health and disease, including their contributions to protection against SARS-CoV-2 and potential contributions to immunopathology associated with COVID-19.


Subject(s)
COVID-19 , Immunologic Memory , CD4-Positive T-Lymphocytes , Humans , SARS-CoV-2
3.
Front Immunol ; 13: 840610, 2022.
Article in English | MEDLINE | ID: covidwho-1775674

ABSTRACT

T lymphocytes (T cells) are divided into two functionally different subgroups the CD4+ T helper cells (Th) and the CD8+ cytotoxic T lymphocytes (CTL). Adequate CD4 and CD8 T cell activation to proliferation, clonal expansion and effector function is crucial for efficient clearance of infection by pathogens. Failure to do so may lead to T cell exhaustion. Upon activation by antigen presenting cells, T cells undergo metabolic reprograming that support effector functions. In this review we will discuss how metabolic reprograming dictates functionality during viral infections using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) as examples. Moreover, we will briefly discuss T cell metabolic programs during bacterial infections exemplified by Mycobacterium tuberculosis (MT) infection.


Subject(s)
CD4-Positive T-Lymphocytes , COVID-19 , CD8-Positive T-Lymphocytes , Humans , SARS-CoV-2 , T-Lymphocytes, Cytotoxic
4.
Arch Microbiol ; 204(5): 242, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1772889

ABSTRACT

The novel virus "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)" has been responsible for the worldwide pandemic causing huge devastation and deaths since December 2019. The disease caused by this virus is known as COVID-19. The present study is based on immuno-informatics approach to develop a multi-epitope-loaded peptide vaccine to combat the COVID-19 menace. Here, we have reported the 9-mer CD8 T cell epitopes and 15-mer CD4 T cell epitopes, free from glycosylation sites, belonging to three proteins, viz. surface glycoprotein, membrane glycoprotein and envelope protein of this virus. Immunogenicity, aliphatic amino acid, antigenicity and hydrophilicity scores of the predicted epitopes were estimated. In addition, other physicochemical parameters, namely net charge, Boman index and amino acid contents, were also accounted. Out of all the epitopes, three CD8 T cell epitopes viz. PDPSKPSKR, DPSKPSKRS and QTQTNSPRR and three CD4 T cell epitopes viz. ASYQTQTNSPRRARS, RIGNYKLNTDHSSSS and RYRIGNYKLNTDHSS were found to be efficient targets for raising immunity in human against this virus. With the help of our identified potent epitopes, various pharma industries might initiate efforts to incorporate those epitopes with carrier protein or adjuvant to develop a multi-epitope-loaded peptide vaccine against SARS-CoV-2. The peptide vaccines are usually cost-effective and therefore, could be administered as a preventive measure to combat the spread of this disease. Proper clinical trials must be conducted prior to the use of identified epitopes as vaccine candidates.


Subject(s)
COVID-19 , Epitopes, T-Lymphocyte , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines , Epitopes, B-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/chemistry , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Subunit
5.
J Virol ; 96(6): e0187321, 2022 03 23.
Article in English | MEDLINE | ID: covidwho-1759293

ABSTRACT

Given the current coronavirus disease 2019 (COVID-19) pandemic, coinfection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) is a major concern for public health. However, the immunopathogenic events occurring with coinfections of SARS-CoV-2 and IAV remain unclear. Here, we report the pathogenic and immunological consequences of SARS-CoV-2 and IAV H1N1 coinfection in the K18-hACE2 transgenic mouse model. Compared with a single infection with SARS-CoV-2 or IAV, coinfections not only prolonged the primary virus infection period but also increased immune cell infiltration and inflammatory cytokine levels in bronchoalveolar lavage fluid leading to severe pneumonia and lung damage. Moreover, coinfections caused severe lymphopenia in peripheral blood, resulting in reduced total IgG, neutralizing antibody titers, and CD4+ T cell responses against each virus. This study sheds light on the immunopathogenesis of SARS-CoV-2 and IAV coinfection, which may guide the development of effective therapeutic strategies for the treatment of patients coinfected with these viruses. IMPORTANCE The cocirculation of influenza virus merging with the COVID-19 pandemic raises a potentially severe threat to public health. Recently, increasing numbers of SARS-CoV-2 and influenza virus coinfection have been reported from many countries. It is a worrisome issue that SARS-CoV-2 coinfection with other pathogens may worsen the clinical outcome and severity of COVID-19 and increase fatality. Here, we evaluated SARS-CoV-2 and IAV coinfection using the K18-hACE2 mouse model. Coinfected mice exhibited increased mortality with prolonged IAV shedding. Furthermore, coinfected mice showed a higher level of cytokines and chemokines than a single infection condition. Interestingly, our data show that coinfected mice showed significantly fewer virus-specific and neutralizing antibodies than the mice with a single infection. Overall, this study suggests that coinfection aggravates viral pathology by impaired neutralizing antibody response.


Subject(s)
COVID-19 , Coinfection , Influenza A Virus, H1N1 Subtype , Influenza A virus , Animals , Antibodies, Neutralizing , CD4-Positive T-Lymphocytes/pathology , Disease Models, Animal , Humans , Mice , Pandemics , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/pathology
6.
Microbiol Spectr ; 10(1): e0169521, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1752774

ABSTRACT

Global control of COVID-19 will require the deployment of vaccines capable of inducing long-term protective immunity against SARS-CoV-2 variants. In this report, we describe an adjuvanted subunit candidate vaccine that affords elevated, sustained, and cross-variant SARS-CoV-2 neutralizing antibodies (NAbs) in multiple animal models. Alhydroxiquim-II is a Toll-Like Receptor (TLR) 7/8 small-molecule agonist chemisorbed on aluminum hydroxide (Alhydrogel). Vaccination with Alhydroxiquim-II combined with a stabilized, trimeric form of the SARS-CoV-2 spike protein (termed CoVac-II) resulted in high-titer NAbs in mice, with no decay in responses over an 8-month period. NAbs from sera of CoVac-II-immunized mice, horses and rabbits were broadly neutralizing against SARS-CoV-2 variants. Boosting long-term CoVac-II-immunized mice with adjuvanted spike protein from the Beta variant markedly increased levels of NAb titers against multiple SARS-CoV-2 variants; notably, high titers against the Delta variant were observed. These data strongly support the clinical assessment of Alhydroxiquim-II-adjuvanted spike proteins to protect against SARS-CoV-2 variants of concern. IMPORTANCE There is an urgent need for next-generation COVID-19 vaccines that are safe, demonstrate high protective efficacy against SARS-CoV-2 variants and can be manufactured at scale. We describe a vaccine candidate (CoVac-II) that is based on stabilized, trimeric spike antigen produced in an optimized, scalable and chemically defined production process. CoVac-II demonstrates strong and persistent immunity after vaccination of mice, and is highly immunogenic in multiple animal models, including rabbits and horses. We further show that prior immunity can be boosted using a recombinant spike antigen from the Beta variant; importantly, plasma from boosted mice effectively neutralize multiple SARS-CoV-2 variants in vitro, including Delta. The strong humoral and Th1-biased immunogenicity of CoVac-II is driven by use of Alhydroxiquim-II (AHQ-II), the first adjuvant in an authorized vaccine that acts through the dual Toll-like receptor (TLR)7 and TLR8 pathways, as part of the Covaxin vaccine. Our data suggest AHQ-II/spike protein combinations could constitute safe, affordable, and mass-manufacturable COVID-19 vaccines for global distribution.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , CD4-Positive T-Lymphocytes/immunology , Horses , Mice , Rabbits , T-Lymphocytes/immunology
7.
Front Immunol ; 13: 835686, 2022.
Article in English | MEDLINE | ID: covidwho-1742218

ABSTRACT

Angiotensin converting enzyme-2 (ACE2) and associated proteins play a pivotal role in various physiological and pathological events, such as immune activation, inflammation, gut barrier maintenance, intestinal stem cell proliferation, and apoptosis. Although many of these clinical events are quite significant in SIV/HIV infection, expression profiling of these proteins has not been well reported. Considering the different pathological consequences in the gut after HIV infection, we hypothesized that the expression of ACE2 and associated proteins of the Renin-angiotensin system (RAS) could be compromised after SIV/HIV infection. We quantified the gene expression of ACE2 as well as AGTR1/2, ADAM17, and TMPRSS2, and compared between SIV infected and uninfected rhesus macaques (Macaca mulatta; hereafter abbreviated RMs). The gene expression analysis revealed significant downregulation of ACE2 and upregulation of AGTR2 and inflammatory cytokine IL-6 in the gut of infected RMs. Protein expression profiling also revealed significant upregulation of AGTR2 after infection. The expression of ACE2 in protein level was also decreased, but not significantly, after infection. To understand the entirety of the process in newly regenerated epithelial cells, a global transcriptomic study of enteroids raised from intestinal stem cells was performed. Interestingly, most of the genes associated with the RAS, such as DPP4, MME, ANPEP, ACE2, ENPEP, were found to be downregulated in SIV infection. HNFA1 was found to be a key regulator of ACE2 and related protein expression. Jejunum CD4+ T cell depletion and increased IL-6 mRNA, MCP-1 and AGTR2 expression may signal inflammation, monocyte/macrophage accumulation and epithelial apoptosis in accelerating SIV pathogenesis. Overall, the findings in the study suggested a possible impact of SIV/HIV infection on expression of ACE2 and RAS-associated proteins resulting in the loss of gut homeostasis. In the context of the current COVID-19 pandemic, the outcome of SARS-CoV-2 and HIV co-infection remains uncertain and needs further investigation as the significance profile of ACE2, a viral entry receptor for SARS-CoV-2, and its expression in mRNA and protein varied in the current study. There is a concern of aggravated SARS-CoV-2 outcomes due to possible serious pathological events in the gut resulting from compromised expression of RAS- associated proteins in SIV/HIV infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , CD4-Positive T-Lymphocytes/immunology , Jejunum/metabolism , Simian Acquired Immunodeficiency Syndrome/metabolism , Simian Immunodeficiency Virus/physiology , Animals , Cells, Cultured , Cytokines/metabolism , Dipeptidyl Peptidase 4/metabolism , Gene Expression Regulation , Humans , Inflammation Mediators , Jejunum/pathology , Macaca mulatta , Receptor, Angiotensin, Type 2/metabolism
8.
Immun Inflamm Dis ; 10(4): e595, 2022 04.
Article in English | MEDLINE | ID: covidwho-1739165

ABSTRACT

BACKGROUND: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses. METHODS: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFNγ) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array. RESULTS: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFNγ and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFNγ in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion. CONCLUSION: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses.


Subject(s)
COVID-19 , SARS-CoV-2 , CD4-Positive T-Lymphocytes , Follow-Up Studies , Humans , Immunity, Cellular , Severity of Illness Index
9.
Virulence ; 13(1): 569-577, 2022 12.
Article in English | MEDLINE | ID: covidwho-1740687

ABSTRACT

We aimed to determine the levels of follicular helper T (Tfh) and follicular regulatory T (Tfr) cells in COVID-19 patients and determine whether their levels correlated with disease severity and presence of hyperglycemia. This study was carried out in 34 hospitalized COVID-19 patients and 20 healthy controls. Levels of total circulating Tfh, inducible T-cell costimulator (ICOS)+ activated Tfh, and Tfr cells were assessed in all participants by flow cytometry. Total CD4+CXCR5+ Tfh cells and ICOS+Foxp3-activated Tfh cells increased and ICOS+Foxp3+ Tfr cells decreased in COVID-19 patients, especially in diabetic patients and those with severe disease. Activated ICOS+ Tfh cells were directly correlated with lactate dehydrogenase, D-dimer, ferritin, and respiratory rate and inversely correlated with the partial pressure of carbon dioxide. COVID-19 is associated with marked activation of Tfh cells and a profound drop in Tfr cells, especially in severe and diabetic patients. Future studies on expanded cohorts of patients are needed to clarify the relationship between SARS-CoV-2 and acute-onset diabetes.


Subject(s)
COVID-19 , Hyperglycemia , CD4-Positive T-Lymphocytes , Humans , SARS-CoV-2 , T-Lymphocytes, Regulatory
10.
Int J Mol Sci ; 23(5)2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1736946

ABSTRACT

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.


Subject(s)
Mycobacterium tuberculosis , Animals , Antigens, Bacterial , BCG Vaccine , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Lymphocytic choriomeningitis virus/genetics , Mice , Mycobacterium tuberculosis/genetics
11.
Front Immunol ; 12: 794638, 2021.
Article in English | MEDLINE | ID: covidwho-1731769

ABSTRACT

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , CD4-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Flow Cytometry/methods , HIV Antibodies/therapeutic use , HIV Infections/drug therapy , HIV-1/physiology , Receptors, CCR5/metabolism , SARS-CoV-2/physiology , Simian Acquired Immunodeficiency Syndrome/drug therapy , Simian Immunodeficiency Virus/physiology , Animals , CD4 Lymphocyte Count , Female , Humans , Primates , Protein Binding , Receptors, CCR5/immunology , Treatment Outcome
12.
Front Immunol ; 12: 804808, 2021.
Article in English | MEDLINE | ID: covidwho-1731770

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19) pandemic is a serious global threat until we identify the effective preventive and therapeutic strategies. SARS-CoV-2 infection is characterized by various immunopathological consequences including lymphocyte activation and dysfunction, lymphopenia, cytokine storm, increased level of neutrophils, and depletion and exhaustion of lymphocytes. Considering the low level of antibody-mediated protection during coronavirus infection, understanding the role of T cell for long-term protection is decisive. Both CD4+ and CD8+ T cell response is imperative for cell-mediated immune response during COVID-19. However, the level of CD8+ T cell response reduced to almost half as compared to CD4+ after 6 months of infection. The long-term protection is mediated via generation of immunological memory response during COVID-19. The presence of memory CD4+ T cells in all the severely infected and recovered individuals shows that the memory response is predominated by CD4+ T cells. Prominently, the antigen-specific CD4+ and CD8+ T cells are specifically observed during day 0 to day 28 in COVID-19-vaccinated individuals. However, level of antigen-specific T memory cells in COVID-19-vaccinated individuals defines the long-term protection against forthcoming outbreaks of SARS-CoV-2.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunologic Memory/immunology , /immunology , Animals , Cytokine Release Syndrome/immunology , Humans
13.
J Immunother Cancer ; 10(3)2022 03.
Article in English | MEDLINE | ID: covidwho-1731296

ABSTRACT

Vaccination against COVID-19 is critical for immuno-compromised individuals, including patients with cancer. Systemic reactogenicity, a manifestation of the innate immune response to vaccines, occurs in up to 69% of patients following vaccination with RNA-based COVID-19 vaccines. Tumor regression can occur following an intense immune-inflammatory response and novel strategies to treat cancer rely on manipulating the host immune system. Here, we report spontaneous regression of metastatic salivary gland myoepithelial carcinoma in a patient who experienced grade 3 systemic reactogenicity, following vaccination with the mRNA-1273 COVID-19 vaccine. Histological and immunophenotypic inspection of the postvaccination lung biopsy specimens showed a massive inflammatory infiltrate with scant embedded tumor clusters (<5%). Highly multiplexed imaging mass cytometry showed that the postvaccination lung metastasis samples had remarkable immune cell infiltration, including CD4+ T cells, CD8+ T cells, natural killer cells, B cells, and dendritic cells, which contrasted with very low levels of these cells in the prevaccination primary tumor and lung metastasis samples. CT scans obtained 3, 6, and 9 months after the second vaccine dose demonstrated persistent tumor shrinkage (50%, 67%, and 73% reduction, respectively), suggesting that vaccination stimulated anticancer immunity. Insight: This case suggests that the mRNA-1273 COVID-19 vaccine stimulated anticancer immunity and tumor regression.


Subject(s)
Immunity, Innate , Immunogenicity, Vaccine , Lung Neoplasms/immunology , Myoepithelioma/immunology , Parotid Neoplasms/surgery , B-Lymphocytes , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Female , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/secondary , Middle Aged , Myoepithelioma/diagnostic imaging , Myoepithelioma/secondary , Parotid Neoplasms/pathology
14.
J Immunol Methods ; 502: 113230, 2022 03.
Article in English | MEDLINE | ID: covidwho-1720358

ABSTRACT

Innate immune mechanisms are central players in response to the binding of pathogens to pattern-recognition receptors providing a crucial initial block on viral replication. Moreover, innate immune response mobilizes cells of the cellular-mediated immune system, which develop into effector cells that promote viral clearance. Here, we observed circulating leukocyte T cell response in healthy subjects, COVID-19 infected, and in healthy vaccinated subjects. We found a significant CD8+ T cells (p < 0,05) decrease and an augmented CD4+/CD8+ ratio (p < 0,05) in COVID-19 infected group compared with vaccinated subjects. In addition, healthy vaccinated subjects have a significant increased expression of CD8+ T cells, and a reduction of CD4+/CD8+ ratio with respect to subjects previously COVID-19 infected. Central Memory and Terminal Effector Memory cells (TEMRA) increased after vaccine but not among groups.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , /immunology , Adult , Aged , CD4-CD8 Ratio , COVID-19/blood , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Case-Control Studies , Cross-Sectional Studies , Female , Healthy Volunteers , Humans , Immunity, Innate , Immunogenicity, Vaccine , Immunophenotyping , Male , Middle Aged , SARS-CoV-2/immunology , Vaccination
15.
Front Immunol ; 12: 820126, 2021.
Article in English | MEDLINE | ID: covidwho-1715000

ABSTRACT

This study aims to assess the immunological response and impact on virological control of the mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among people living with HIV (PLWH). In this single-center observational study, all PLWH were offered vaccination with mRNA1273 or BNT162b2. Both anti-N and anti-S1-receptor binding domain (RBD) antibodies were measured together with HIV-1 RNA levels after the first dose (M0) and then at 1 (M1), 2 (M2) and 6 (M6) months later. A total of 131 individuals (median age: 54 years [IQR: 47.0-60.5]; male: 70.2%; median baseline CD4 T-cell: 602/µl [IQR 445.0-825.5]; median nadir CD4 T-cells 223/µl [IQR 111.0-330.0]) were included. All participants were positive for anti-RBD antibodies at 30 days, 60 days and 6 months after the first dose, with no statistical difference between those with HIV-1 RNA below or >20 copies/ml. HIV-1 RNA data were collected for 128 patients at baseline and 30 days after the first dose; for 124 individuals, 30 days after the second dose; and for 83 patients, 6 months after the first dose. Nineteen (14.8%) of 128 had detectable HIV-1 RNA (>20 copies/ml) at M0, 13/128 (10.2%) at M1 (among which 5 were newly detectable), 15/124 (12.1%) at M2 (among which 5 were newly detectable), and 8/83 (9.6%) at M6. No serious adverse effects were reported. All participants elicited antibodies after two doses of mRNA vaccines, with only a minor impact on HIV-1 RNA levels over a 6-month period.


Subject(s)
/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , HIV Infections/immunology , HIV-1/physiology , RNA, Viral/analysis , SARS-CoV-2/physiology , Adult , Aged , Antibodies, Viral/blood , Antibody Formation , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunity, Heterologous , Male , Middle Aged , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
16.
Viruses ; 14(3)2022 03 02.
Article in English | MEDLINE | ID: covidwho-1715786

ABSTRACT

BACKGROUND: Examination of CD4+ T cell responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection offers useful information for the improvement of vaccination strategies against this virus and the protective effect of these T cells. METHODS: We characterized the SARS-CoV-2-specific CD4+ T cell activation marker, multifunctional cytokine and cytotoxic marker expression in recovered coronavirus disease 2019 (COVID-19) individuals. RESULTS: CD4+ T-cell responses in late convalescent (>6 months of diagnosis) individuals are characterized by elevated frequencies of activated as well as mono, dual- and multi-functional Th1 and Th17 CD4+ T cells in comparison to early convalescent (<1 month of diagnosis) individuals following stimulation with SARS-CoV-2-specific antigens. Similarly, the frequencies of cytotoxic marker expressing CD4+ T cells were also enhanced in late convalescent compared to early convalescent individuals. CONCLUSION: Our findings from a low-to middle-income country suggest protective adaptive immune responses following natural infection of SARS-CoV-2 are elevated even at six months following initial symptoms, indicating the CD4+ T cell mediated immune protection lasts for six months or more in natural infection.


Subject(s)
COVID-19 , CD4-Positive T-Lymphocytes , Humans , Immunity, Humoral , Lymphocyte Activation , SARS-CoV-2
17.
Microbiol Spectr ; 10(1): e0084521, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1709405

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the stimulatory levels of cellular-mediated immunity, which plays an essential role in controlling SARS-CoV-2 infection. In fact, several studies have shown the association of lymphopenia with severe COVID-19 in patients. The aim of this study is to investigate the response of the immune system, including cell-mediated immunity and antibody production, during different stages of SARS-CoV-2 infection. Peripheral blood and serum samples were collected from patients with moderate infection, patients under medication (hospitalized), patients who had recovered, and healthy individuals (n = 80). Flow cytometry analysis was performed on peripheral blood samples to determine the cellular immunity profile of each patient. The data showed a significant reduction in the levels of CD3+, CD4+, and CD8+ T cells and CD45+ cells in the moderate and under-medication groups, suggesting lymphopenia in those patients. Also, enzyme-linked immunosorbent assay (ELISA) was conducted on the serum samples to measure the levels of antibodies, including IgM and IgG, in each patient. The results revealed a significant increase in the levels of IgM in the moderate infection and under-medication patients, thus indicating the production of IgM during the first week of infection. Furthermore, changes in the levels of IgG were significantly detected among recovered patients, indicating therefore a remarkable increase during the recovery stage of SARS-CoV-2 infection and thus a strong humoral-mediated immunity. In summary, the results of this study may help us to understand the main role of the cellular immune responses, including CD3+, CD4+, and CD8+ T cells, against SARS-CoV-2 infection. This understanding might support the development of SARS-CoV-2 treatments and vaccines in the near future. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 in China. This virus is a serious threat to people not only in China but also worldwide, where it has been detected in over 222 countries. It has been reported that ∼3.4% of SARS-CoV-2-infected patients have died. The significance of our study relies on the fact that an enzyme-linked immunosorbent assay and flow cytometry were used to measure the levels of antibodies and cellular immune response, respectively, from clinical samples of patients infected with SARS-CoV-2.


Subject(s)
CD3 Complex/blood , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , COVID-19/immunology , Immunoglobulin G/blood , Immunoglobulin M/blood , Adult , Aged , Aged, 80 and over , COVID-19/blood , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Young Adult
19.
Am J Physiol Heart Circ Physiol ; 322(4): H568-H574, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1706188

ABSTRACT

The prevalence of major depressive disorder (MDD) is highest in young adulthood, an effect that has been magnified by the COVID-19 pandemic. Importantly, individuals with MDD are at a greater risk of developing cardiovascular disease (CVD). Accumulating evidence supports immune system dysregulation as a major contributor to the elevated CVD risk in older adults with MDD; however, whether this is present in young adults with MDD without comorbid disease remains unclear. Interestingly, recent data suggest augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) as a potent driver of immune dysregulation in animal models of psychiatric disease. With this background in mind, we tested the hypothesis that young adults with MDD would have augmented T-cell mitoROS and circulating proinflammatory cytokines compared with healthy young adults without MDD (HA). Whole blood was drawn from 14 young adults with MDD (age: 23 ± 2 yr) and 11 HA (age: 22 ± 1 yr). T-cell mitoROS (MitoSOX red; total: CD3+, T-helper: CD4+, T cytotoxic: CD8+) and serum cytokines were assessed by flow cytometry. Total T-cell mitoROS was significantly greater in adults with MDD compared with HA [median: 14,089 arbitrary units (AU); median: 1,362 AU, P = 0.01]. Likewise, both T-helper and T-cytotoxic cell mitoROS were significantly greater in adults with MDD compared with HA (both: P < 0.05). There were no differences in circulating cytokines between groups (all cytokines: P > 0.05). Collectively, these findings suggest that elevated T-cell mitoROS may represent an early marker of immune system dysregulation in young, otherwise healthy, adults with MDD.NEW & NOTEWORTHY To our knowledge, we provide the first evidence of augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) in young, otherwise healthy adults with MDD. Although the elevated T-cell mitoROS did not correspond to a proinflammatory profile, these findings suggest that elevated T-cell mitoROS may be an early marker of immune system dysregulation in young adults with MDD.


Subject(s)
Depressive Disorder, Major/immunology , Mitochondria/chemistry , Reactive Oxygen Species/analysis , T-Lymphocytes/ultrastructure , Adult , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , COVID-19/immunology , COVID-19/psychology , Cytokines , Female , Humans , Ki-1 Antigen/analysis , Male , SARS-CoV-2 , Severity of Illness Index , Young Adult
20.
Front Immunol ; 13: 817905, 2022.
Article in English | MEDLINE | ID: covidwho-1699973

ABSTRACT

The duration of humoral and cellular immune memory following SARS-CoV-2 infection in populations in least developed countries remains understudied but is key to overcome the current SARS-CoV-2 pandemic. Sixty-four Cambodian individuals with laboratory-confirmed infection with asymptomatic or mild/moderate clinical presentation were evaluated for Spike (S)-binding and neutralizing antibodies and antibody effector functions during acute phase of infection and at 6-9 months follow-up. Antigen-specific B cells, CD4+ and CD8+ T cells were characterized, and T cells were interrogated for functionality at late convalescence. Anti-S antibody titers decreased over time, but effector functions mediated by S-specific antibodies remained stable. S- and nucleocapsid (N)-specific B cells could be detected in late convalescence in the activated memory B cell compartment and are mostly IgG+. CD4+ and CD8+ T cell immune memory was maintained to S and membrane (M) protein. Asymptomatic infection resulted in decreased antibody-dependent cellular cytotoxicity (ADCC) and frequency of SARS-CoV-2-specific CD4+ T cells at late convalescence. Whereas anti-S antibodies correlated with S-specific B cells, there was no correlation between T cell response and humoral immune memory. Hence, all aspects of a protective immune response are maintained up to nine months after SARS-CoV-2 infection and in the absence of re-infection.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , SARS-CoV-2/immunology , B-Lymphocytes/immunology , COVID-19/pathology , Cambodia , Coronavirus Nucleocapsid Proteins/immunology , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology
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