Human MAIT cells respond to and suppress HIV-1

Human MAIT cells sit at the interface between innate and adaptive immunity, are polyfunctional and are capable of killing pathogen infected cells via recognition of the Class IB molecule MR1. MAIT cells have recently been shown to possess an antiviral protective role in vivo and we therefore sought to explore this in relation to HIV-1 infection. There was marked activation of MAIT cells in vivo in HIV-1-infected individuals, which decreased following ART. Stimulation of THP1 monocytes with R5 tropic HIVBAL potently activated MAIT cells in vitro. This activation was dependent on IL-12 and IL-18 but was independent of the TCR. Upon activation, MAIT cells were able to upregulate granzyme B, IFNγ and HIV-1 restriction factors CCL3, 4, and 5. Restriction factors produced by MAIT cells inhibited HIV-1 infection of primary PBMCs and immortalized target cells in vitro. These data reveal MAIT cells to be an additional T cell population responding to HIV-1, with a potentially important role in controlling viral replication at mucosal sites

Human MAIT cells respond to and suppress HIV-1

Human MAIT cells sit at the interface between innate and adaptive immunity, are polyfunctional and are capable of killing pathogen infected cells via recognition of the Class IB molecule MR1. MAIT cells have recently been shown to possess an antiviral protective role in vivo and we therefore sought to explore this in relation to HIV-1 infection. There was marked activation of MAIT cells in vivo in HIV-1-infected individuals, which decreased following ART. Stimulation of THP1 monocytes with R5 tropic HIV(BAL) potently activated MAIT cells in vitro. This activation was dependent on IL-12 and IL-18 but was independent of the TCR. Upon activation, MAIT cells were able to upregulate granzyme B, IFNγ and HIV-1 restriction factors CCL3, 4, and 5. Restriction factors produced by MAIT cells inhibited HIV-1 infection of primary PBMCs and immortalized target cells in vitro. These data reveal MAIT cells to be an additional T cell population responding to HIV-1, with a potentially important role in controlling viral replication at mucosal sites

Physical activity, sedentary time and physical capability in early old age: British birth cohort study.

PURPOSE: To investigate the associations of time spent sedentary, in moderate-to-vigorous-intensity physical activity (MVPA) and physical activity energy expenditure (PAEE) with physical capability measures at age 60-64 years. METHODS: Time spent sedentary and in MVPA and, PAEE were assessed using individually calibrated combined heart rate and movement sensing among 1727 participants from the MRC National Survey of Health and Development in England, Scotland and Wales as part of a detailed clinical assessment undertaken in 2006-2010. Multivariable linear regression models were used to examine the cross-sectional associations between standardised measures of each of these behavioural variables with grip strength, chair rise and timed up-&-go (TUG) speed and standing balance time. RESULTS: Greater time spent in MVPA was associated with higher levels of physical capability; adjusted mean differences in each capability measure per 1 standard deviation increase in MVPA time were: grip strength (0.477 kg, 95% confidence interval (CI): 0.015 to 0.939), chair rise speed (0.429 stands/min, 95% CI: 0.093 to 0.764), standing balance time (0.028 s, 95% CI: 0.003 to 0.053) and TUG speed (0.019 m/s, 95% CI: 0.011 to 0.026). In contrast, time spent sedentary was associated with lower grip strength (-0.540 kg, 95% CI: -1.013 to -0.066) and TUG speed (-0.011 m/s, 95% CI: -0.019 to -0.004). Associations for PAEE were similar to those for MVPA. CONCLUSION: Higher levels of MVPA and overall physical activity (PAEE) are associated with greater levels of physical capability whereas time spent sedentary is associated with lower levels of capability. Future intervention studies in older adults should focus on both the promotion of physical activity and reduction in time spent sedentary.This work was supported by the UK Medical Research Council (U120063239, U123092720, MC_UU_12019/1, MC_UU_12019/4, MC_UU_12015/3, and MC_UU_12015/4).This is the final published version. It first appeared at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126465

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal coronavirus disease (COVID-19) outcomes is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses, and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses.

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal coronavirus disease (COVID-19) outcomes is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses, and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants

TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells

Mucosal-associated invariant T (MAIT) cells are an abundant innate-like T lymphocyte population that are enriched in liver and mucosal tissues. They are restricted by MR1, which presents antigens derived from a metabolic precursor of riboflavin synthesis, a pathway present in many microbial species, including commensals. Therefore, MR1-mediated MAIT cell activation must be tightly regulated to prevent inappropriate activation and immunopathology. Using an in vitro model of MR1-mediated activation of primary human MAIT cells, we investigated the mechanisms by which it is regulated. Uptake of intact bacteria by antigen presenting cells (APCs) into acidified endolysosomal compartments was required for efficient MR1-mediated MAIT cell activation, while stimulation with soluble ligand was inefficient. Consistent with this, little MR1 was seen at the surface of human monocytic (THP1) and B-cell lines. Activation with a TLR ligand increased the amount of MR1 at the surface of THP1 but not B-cell lines, suggesting differential regulation in different cell types. APC activation and NF-κB signaling were critical for MR1-mediated MAIT cell activation. In primary cells, however, prolonged TLR signaling led to downregulation of MR1-mediated MAIT cell activation. Overall, MR1-mediated MAIT cell activation is a tightly regulated process, dependent on integration of innate signals by APCs

TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells

Mucosal-associated invariant T (MAIT) cells are an abundant innate-like T lymphocyte population that are enriched in liver and mucosal tissues. They are restricted by MR1, which presents antigens derived from a metabolic precursor of riboflavin synthesis, a pathway present in many microbial species, including commensals. Therefore, MR1-mediated MAIT cell activation must be tightly regulated to prevent inappropriate activation and immunopathology. Using an in vitro model of MR1-mediated activation of primary human MAIT cells, we investigated the mechanisms by which it is regulated. Uptake of intact bacteria by antigen presenting cells (APCs) into acidified endolysosomal compartments was required for efficient MR1-mediated MAIT cell activation, while stimulation with soluble ligand was inefficient. Consistent with this, little MR1 was seen at the surface of human monocytic (THP1) and B-cell lines. Activation with a TLR ligand increased the amount of MR1 at the surface of THP1 but not B-cell lines, suggesting differential regulation in different cell types. APC activation and NF-κB signaling were critical for MR1-mediated MAIT cell activation. In primary cells, however, prolonged TLR signaling led to downregulation of MR1-mediated MAIT cell activation. Overall, MR1-mediated MAIT cell activation is a tightly regulated process, dependent on integration of innate signals by APCs

Molecular analyses define Vα7.2-Jα33+ MAIT-cell depletion in HIV infection: a case-control study

MAIT-cells are an abundant anti-bacterial innate-like lymphocyte population. There are conflicting reports as to their fate in HIV infection. In this case-control study, we used quantitative real-time PCR to assess the abundance of mRNA and genomic DNA encoding the canonical MAIT-cell T-cell receptor (Vα7.2-Jα33) in healthy controls and HIV-infected patients. Significant depletion of both Vα7.2-Jα33 mRNA and gDNA was seen in HIV infection. Depletion of Vα7.2+CD161++ T-cells was confirmed by flow cytometry. The abundance of Vα7.2-Jα33 mRNA correlated most strongly with the frequency of Vα7.2+CD161++ cells. No increase was observed in the frequency of Vα7.2+CD161- cells amongst CD3+CD4- lymphocytes. Therefore MAIT-cells are depleted from blood in HIV infection as confirmed by independent assays. Molecular approaches represent a suitable alternative to flow cytometry-based assays for tracking of MAIT-cells in HIV and other settings

Lack of effect of Maraviroc intensification on blood and gut reservoir.

We show that intensification of treatment with maraviroc in patients chronically infected with HIV-1 receiving successful long-term ART was not associated with improvements in HIV related morbidity, HIV reservoir, microbial translocation, immune activation or immune exhaustion in either gut or peripheral blood. The measurement of reservoir in both gut and blood longitudinally contributes to a paucity of data in the area