| 1. |
- Saeidi, Alireza, et al.
(författare)
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Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8(+) T cells in HIV/TB co-infection
- 2015
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Ingår i: Cellular Immunology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0008-8749 .- 1090-2163. ; 297:1, s. 19-32
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Tidskriftsartikel (refereegranskat)abstract
- The role of T-cell immunosenescence and functional CD8(+) T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of CD38, a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8(+) T cells. Up-regulation of CD57 and CD38 were directly proportional to lack of co-stimulatory markers on CD8(+) T cells, besides diminished expression of CD127 (IL-7R alpha) on CD57(+)CD4(+) T cells. Notably, intracellular IFN-gamma, perforin and granzyme B levels in HIV-specific CD8(+) T cells of HIV/TB co-infected subjects were diminished. Intracellular CD57 levels in HIV gag p24-specific CD8(+) T cells were significantly increased in HIV/TB co-infection. We suggest that HIV-TB co-infection contributes to senescence associated with chronic immune activation, which could be due to functional insufficiency of CD8(+) T cells. (C) 2015 Elsevier Inc. All rights reserved.
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| 2. |
- Ahmad, Fareed, et al.
(författare)
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Negative Checkpoint Regulatory Molecule 2B4 (CD244) Upregulation Is Associated with Invariant Natural Killer T Cell Alterations and Human Immunodeficiency Virus Disease Progression
- 2017
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The CD1d-restricted invariant natural killer T (iNKT) cells are implicated in innate immune responses against human immunodeficiency virus (HIV). However, the determinants of cellular dysfunction across the iNKT cells subsets are seldom defined in HIV disease. Herein, we provide evidence for the involvement of the negative checkpoint regulator (NCR) 2B4 in iNKT cell alteration in a well-defined cohort of HIV-seropositive anti-retroviral therapy (ART) naive, ART-treated, and elite controllers (ECs). We report on exaggerated 2B4 expression on iNKT cells of HIV-infected treatment-naive individuals. In sharp contrast to CD4-iNKT cells, 2B4 expression was significantly higher on CD4+ iNKT cell subset. Notably, an increased level of 2B4 on iNKT cells was strongly correlated with parameters associated with HIV disease progression. Further, iNKT cells from ARTnaive individuals were defective in their ability to produce intracellular IFN-gamma Together, our results suggest that the levels of 2B4 expression and the downstream co-inhibitory signaling events may contribute to impaired iNKT cell responses.
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| 3. |
- Ansari, Abdul W., et al.
(författare)
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Brief Report: Diminished Coinhibitory Molecule 2B4 Expression Is Associated With Preserved iNKT Cell Phenotype in HIV Long-Term Nonprogressors
- 2020
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Ingår i: Journal of Acquired Immune Deficiency Syndromes. - : LIPPINCOTT WILLIAMS & WILKINS. - 1525-4135 .- 1944-7884. ; 85:1, s. 73-78
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously shown an association of elevated coinhibitory molecule 2B4 expression with iNKT cells alterations in HIV disease. Herein, we show a comparative analysis of 2B4 expression on iNKT cells of HIV long-term nonprogressors (LTNPs) and progressors. Methods: Antiretroviral therapy-naive HIV-seropositive individuals (progressors, n = 16) and LTNPs (n = 10) were recruited for this study. We used multicolor flow cytometry on frozen peripheral blood mononuclear cells to determine iNKT subset frequencies, the levels of coinhibitory 2B4 expression, and intracellular interferon-gamma (IFN-gamma) production. CD1d tetramer was used to characterize iNKT cells. Results: We report significantly lower level of 2B4 expression on bulk LTNPs iNKT cells and on their CD4 subsets compared with HIV progressors. Furthermore, the iNKT cells from LTNPs produced higher amount of IFN-gamma than HIV progressors as detected by intracellular cytokine staining. Interestingly, the frequency of 2B4(+)iNKT cells of progressors but not LTNPs significantly correlates with CD4 T-cell count, HIV viral load, and IFN-gamma(+)production by iNKT cells. Conclusion: Our results suggest that in addition to suppressed HIV replication, diminished 2B4 expression and associated coinhibitory signaling, and substantial production of IFN-gamma could contribute to preserved iNKT cell phenotype in LTNPs.
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| 4. |
- Barathan, Muttiah, et al.
(författare)
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Peripheral loss of CD8(+)CD161(++)TCRV7 center dot 2(+) mucosal-associated invariant T cells in chronic hepatitis C virus-infected patients
- 2016
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Ingår i: European Journal of Clinical Investigation. - : WILEY-BLACKWELL. - 0014-2972 .- 1365-2362. ; 46:2, s. 170-180
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMucosal-associated invariant T (MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear. Materials and methodsWe investigated the frequency of CD8(+)CD161(++)TCR V7.2(+) MAIT cells in a cross-sectional cohort of chronic HCV-infected patients (n = 25) and healthy controls (n = 25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing (CCR5 and CD103), biomarkers of immune exhaustion (PD-1, TIM-3 and CTLA-4), chronic immune activation (CD38 and HLA-DR), and immunosenescence (CD57) by flow cytometry. ResultsThe frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of HCV-infected patients. Decrease of CCR5 on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV-infected patients. MAIT cells also showed significantly increased levels of HLA-DR, CD38, PD-1, TIM-3 and CTLA-4, besides CD57 in chronic HCV disease. ConclusionsImmune exhaustion and senescence of CD8(+)CD161(++)TCR V7.2(+) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.
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| 5. |
- Barathan, Muttiah, et al.
(författare)
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Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion
- 2018
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 7:10
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Forskningsöversikt (refereegranskat)abstract
- Hepatitis C virus (HCV) represents a challenging global health threat to similar to 200 million infected individuals. Clinical data suggest that only similar to 10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence, which includes, but is not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here we discuss a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.
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| 6. |
- Preeyaa, Sathappan U., et al.
(författare)
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Peripheral Follicular T Helper Cells and Mucosal-Associated Invariant T Cells Represent Activated Phenotypes During the Febrile Phase of Acute Dengue Virus Infection
- 2020
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Ingår i: Viral immunology. - : MARY ANN LIEBERT, INC. - 0882-8245 .- 1557-8976. ; 33:9, s. 610-615
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral follicular helper T (pTfh) cells represent specialized CD4(+)T cells that help B cells to secrete antibodies. Dengue infection appears to cause immune activation in a wide array of immune cells. Herein, we investigated the signatures of immune activation of circulating Tfh cells and mucosal-associated invariant T (MAIT) cells in adult subjects with confirmed acute clinical dengue virus (DENV) infection by multiparametric flow cytometry. The acute DENV infection induced a significant expansion and activation of pTfh cells and circulating MAIT cells during acute febrile infection. We found a higher frequency of activated PD-1(+)Tfh cells and CD38(+)pTfh cells in clinical DENV infection. We also found similar activated and expanding phenotypes of MAIT cells in the patients tested. The numbers of activated pTfh cells and circulating MAIT cells were higher in dengue patients relative to healthy controls. We concluded that pTfh cells and circulating MAIT cells represent activated phenotypes in acute DENV infection.
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| 7. |
- Saeidi, Alireza, et al.
(författare)
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Attrition of TCR Va7.2+CD161++ MAIT Cells in HIV-Tuberculosis Co-Infection Is Associated with Elevated Levels of PD-1 Expression
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:4, s. e0124659-
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8+ T cells co-expressing the semi-invariant TCR V alpha 7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161++ CD8+ T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naive HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naive HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono-and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono-and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses.
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| 8. |
- Saeidi, Alireza, et al.
(författare)
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Functional role of mucosal-associated invariant T cells in HIV infection
- 2016
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Ingår i: Journal of Leukocyte Biology. - : FEDERATION AMER SOC EXP BIOL. - 0741-5400 .- 1938-3673. ; 100:2, s. 305-314
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Forskningsöversikt (refereegranskat)abstract
- MAIT cells represent an evolutionarily conserved, MR1-restricted, innate-like cell subset that express high levels of CD161; have a canonical semi-invariant TCR iV alpha 7.2; and may have an important role in mucosal immunity against various bacterial and fungal pathogens. Mature MAIT cells are CD161(hi)PLZF(hi)IL-18R alpha(+)iV alpha 7.2(+)gamma delta-CD3(+)CD8(+) T cells and occur in the peripheral blood, liver, and mucosa of humans. MAIT cells are activated by a metabolic precursor of riboflavin synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial properties, their functional role in persistent viral infections is poorly understood. Although there is an increasing line of evidence portraying the depletion of MAIT cells in HIV disease, the magnitude and the potential mechanisms underlying such depletion remain unclear. Recent studies suggest that MAIT cells are vulnerable to immune exhaustion as a consequence of HIV and hepatitis C virus infections and HIV/tuberculosis coinfections. HIV infection also appears to cause functional depletion of MAIT cells resulting from abnormal expression of T-bet and EOMES, and effective ART is unable to completely salvage functional MAIT cell loss. Depletion and exhaustion of peripheral MAIT cells may affect mucosal immunity and could increase susceptibility to opportunistic infections during HIV infection. Here, we review some of the important mechanisms associated with depletion and functional loss of MAIT cells and also suggest potential immunotherapeutic strategies to restore MAIT cell functions, including the use of IL-7 to restore effector functions in HIV disease.
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| 9. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Clinical characteristics and novel mutations of omicron subvariant XBB in Tamil Nadu, India - a cohort study
- 2023
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Ingår i: The Lancet Regional Health - Southeast Asia. - : ELSEVIER. - 2772-3682. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background Despite the continued vaccination efforts, there had been a surge in breakthrough infections, and the emergence of the B.1.1.529 omicron variant of SARS-CoV-2 in India. There is a paucity of information globally on the role of newer XBB variants in community transmission. Here, we investigated the mutational patterns among hospitalised patients infected with the XBB omicron sub-variant, and checked if there was any association between the rise in the number of COVID-19 cases and the observed novel mutations in Tamil Nadu, India. Methods Nasopharyngeal and oropharyngeal swabs, collected from symptomatic and asymptomatic COVID-19 patients were subjected to real-time PCR followed by Next Generation Sequencing (NGS) to rule out the ambiguity of mutations in viruses isolated from the patients (n = 98). Using the phylogenetic association, the mutational patterns were used to corroborate clinico-demographic characteristics and disease severity among the patients. Findings Overall, we identified 43 mutations in the S gene across 98 sequences, of which two were novel mutations (A27S and T747I) that have not been reported previously with XBB sub-variants in the available literature. Additionally, the XBB sequences from our cohort had more mutations than omicron B.1.1.529. The phylogenetic analysis comprising six major branches clearly showed convergent evolution of XBB. Our data suggests that age, and underlying conditions (e.g., diabetes, hypertension, and cardiovascular disease) or secondary complications confers increased susceptibility to infection rather than vaccination status or prior exposure. Many vaccinated individuals showed evidence of a breakthrough infection, with XBB.3 being the predominant variant identified in the study population. Interpretation Our study indicates that the XBB variant is highly evasive from available vaccines and may be more transmissible, and potentially could emerge as the 'next' predominant variant, which likely could overwhelm the existing variants of SARS-CoV-2 omicron variants.Funding National Health Mission (India), SIDA SARC, VINNMER (Sweden), ORIP/NIH (USA).Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 10. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Genomic surveillance of omicron B.1.1.529 SARS‐CoV‐2 and its variants between December 2021 and March 2023 in Tamil Nadu, India—A state‐wide prospective longitudinal study
- 2024
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Ingår i: Journal of Medical Virology. - : John Wiley & Sons. - 0146-6615 .- 1096-9071. ; 96:2
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Tidskriftsartikel (refereegranskat)abstract
- A state-wide prospective longitudinal investigation of the genomic surveillance of the omicron B.1.1.529 SARS-CoV-2 variant and its sublineages in Tamil Nadu, India, was conducted between December 2021 and March 2023. The study aimed to elucidate their mutational patterns and their genetic interrelationship in the Indian population. The study identified several unique mutations at different time-points, which likely could attribute to the changing disease characteristics, transmission, and pathogenicity attributes of omicron variants. The study found that the omicron variant is highly competent in its mutating potentials, and that it continues to evolve in the general population, likely escaping from natural as well as vaccine-induced immune responses. Our findings suggest that continuous surveillance of viral variants at the global scenario is warranted to undertake intervention measures against potentially precarious SARS-CoV-2 variants and their evolution.
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