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Mucosal-associated invariant T (MAIT) cells are unconventional T cells with innate-like antimicrobial responsiveness. MAIT cells are known for MR1 (MHC class I-related protein 1)-restricted recognition of microbial riboflavin metabolites giving them the capacity to respond to a broad range of microbes. However, recent progress has shown that MAIT cells can also respond to several viral infections in humans and in mouse models, ranging from HIV-1 and hepatitis viruses to influenza virus and SARS-CoV-2, in a primarily cognate Ag-independent manner. Depending on the disease context MAIT cells can provide direct or indirect antiviral protection for the host and may help recruit other immune cells, but they may also in some circumstances amplify inflammation and aggravate immunopathology. Furthermore, chronic viral infections are associated with varying degrees of functional and numerical MAIT cell impairment, suggesting secondary consequences for host defense. In this review, we summarize recent progress and highlight outstanding questions regarding the emerging role of MAIT cells in antiviral immunity.

Chronic inflammation associated with monocyte activation has been linked to HIV-related cognitive outcomes in resource-rich settings. Few studies have investigated this relationship in the African context where endemic non-HIV infections may modulate effects. We characterized immune activation biomarkers in Kenyan and Ugandan participants in relation to neuropsychological testing performance (NTP) from the African Cohort Study (AFRICOS). We focused on activation markers associated with monocytes (sCD14, sCD163, neopterin), T cells (HLA-DR+CD38+ on CD4+ and CD8+ T lymphocytes), and microbial translocation (intestinal fatty acid-binding protein, I-FABP). The HIV-infected (n = 290) vs. HIV-uninfected (n = 104) groups were similar in age with mean (SD) of 41 (9.5) vs. 39 (9.9) years, respectively (p = 0.072). Among HIV-infected participants, the mean (SD) current CD4+ count was 402 (232); 217 (75%) were on combination antiretroviral therapy (cART) and 199 (69%) had suppressed plasma HIV RNA. sCD14 was inversely correlated to NTP (r = - 0.14, p = 0.037) in models that included both HIV-infected and uninfected individuals, adjusted for HIV status and research site, whereas sCD163 was not (r = 0.041, p = 0.938). Neither of the T cell activation markers correlated with NTP. In the HIV-infected group, I-FABP was inversely associated with NTP (r = - 0.147, p = 0.049), even among those with suppressed plasma virus (r = - 0.0004, p = 0.025). Among the full group, HIV status did not appear to modulate the effects observed. In this cohort from East Africa, sCD14, but not sCD163, is associated with cognitive performance regardless of HIV status. Findings among both HIV-infected and HIV-uninfected groups is supportive that HIV and non-HIV-related inflammatory sources contribute to cognitive performance in this setting.

Mucosa-associated invariant T (MAIT) cell loss in chronic HIV-1 infection is a significant insult to antimicrobial immune defenses. Here we investigate the response of MAIT cells during acute HIV-1 infection utilizing the RV217 cohort with paired longitudinal pre- and post-infection samples. MAIT cells are activated and expand in blood and mucosa coincident with peak HIV-1 viremia, in a manner associated with emerging microbial translocation. This is followed by a phase with elevated function as viral replication is controlled to a set-point level, and later by their functional decline at the onset of chronic infection. Interestingly, enhanced innate-like pathways and characteristics develop progressively in MAIT cells during infection, in parallel with TCR repertoire alterations. These findings delineate the dynamic MAIT cell response to acute HIV-1 infection, and show how the MAIT compartment initially responds and expands with enhanced function, followed by progressive reprogramming away from TCR-dependent antibacterial responses towards innate-like functionality.

CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of β-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFNγ and β-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues.

Inhibitory receptors have been extensively described for their importance in regulating immune responses in chronic infections and cancers. Blocking the function of inhibitory receptors such as PD-1, CTLA-4, 2B4, Tim-3, and LAG-3 has shown promise for augmenting CD8 T cell activity and boosting pathogen-specific immunity. However, the prevalence of inhibitory receptors on CD4 T cells and their relative influence on CD4 T cell functionality in chronic HIV infection remains poorly described. We therefore determined and compared inhibitory receptor expression patterns of 2B4, CTLA-4, LAG-3, PD-1, and Tim-3 on virus-specific CD4 and CD8 T cells in relation to their functional T cell profile. In chronic HIV infection, inhibitory receptor distribution differed markedly between cytokine-producing T cell subsets with, gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing cells displaying the highest and lowest prevalence of inhibitory receptors, respectively. Blockade of inhibitory receptors differentially affected cytokine production by cells in response to staphylococcal enterotoxin B stimulation. CTLA-4 blockade increased IFN-γ and CD40L production, while PD-1 blockade strongly augmented IFN-γ, interleukin-2 (IL-2), and TNF-α production. In a Friend retrovirus infection model, CTLA-4 blockade in particular was able to improve control of viral replication. Together, these results show that inhibitory receptor distribution on HIV-specific CD4 T cells varies markedly with respect to the functional subset of CD4 T cells being analyzed. Furthermore, the differential effects of receptor blockade suggest novel methods of immune response modulation, which could be important in the context of HIV vaccination or therapeutic strategies.IMPORTANCE Inhibitory receptors are important for limiting damage by the immune system during acute infections. In chronic infections, however, their expression limits immune system responsiveness. Studies have shown that blocking inhibitory receptors augments CD8 T cell functionality in HIV infection, but their influence on CD4 T cells remains unclear. We assessed the expression of inhibitory receptors on HIV-specific CD4 T cells and their relationship with T cell functionality. We uncovered differences in inhibitory receptor expression depending on the CD4 T cell function. We also found differences in functionality of CD4 T cells following blocking of different inhibitory receptors, and we confirmed our results in a Friend virus retroviral model of infection in mice. Our results show that inhibitory receptor expression on CD4 T cells is linked to CD4 T cell functionality and could be sculpted by blockade of specific inhibitory receptors. These data reveal exciting possibilities for the development of novel treatments and immunotherapeutics.

The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5+ CD4+ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5+ CD4+ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5+ CD4+ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5+ CD4+ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors.IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5+ CD4+ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.

Humoral immunity is critical for viral control, but the identity and mechanisms regulating human antiviral B cells are unclear. Here, we characterized human B cells expressing T-bet and analyzed their dynamics during viral infections. T-bet+ B cells demonstrated an activated phenotype, a distinct transcriptional profile, and were enriched for expression of the antiviral immunoglobulin isotypes IgG1 and IgG3. T-bet+ B cells expanded following yellow fever virus and vaccinia virus vaccinations and also during early acute HIV infection. Viremic HIV-infected individuals maintained a large T-bet+ B cell population during chronic infection that was associated with increased serum and cell-associated IgG1 and IgG3 expression. The HIV gp140-specific B cell response was dominated by T-bet-expressing memory B cells, and we observed a concomitant biasing of gp140-specific serum immunoglobulin to the IgG1 isotype. These findings suggest that T-bet induction promotes antiviral immunoglobulin isotype switching and development of a distinct T-bet+ B cell subset that is maintained by viremia and coordinates the HIV Env-specific humoral response.

The safety and immunogenicity of the two-dose Ebola vaccine regimen MVA-BN-Filo, Ad26.ZEBOV, 14 days apart, was evaluated in people without HIV (PWOH) and living with HIV (PLWH). In this observer-blind, placebo-controlled, phase 2 trial, healthy adults were randomized (4:1) to receive MVA-BN-Filo (dose 1) and Ad26.ZEBOV (dose 2), or two doses of saline/placebo, administered intramuscularly 14 days apart. The primary endpoints were safety (adverse events (AEs)) and immunogenicity (Ebola virus (EBOV) glycoprotein-specific binding antibody responses). Among 75 participants (n = 50 PWOH; n = 25 PLWH), 37% were female, the mean age was 44 years, and 56% were Black/African American. AEs were generally mild/moderate, with no vaccine-related serious AEs. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody responder rates were 100% among PWOH and 95% among PLWH; geometric mean antibody concentrations were 6286 EU/mL (n = 36) and 2005 EU/mL (n = 19), respectively. A total of 45 neutralizing and other functional antibody responses were frequently observed. Ebola-specific CD4+ and CD8+ T-cell responses were polyfunctional and durable to at least 12 months post-dose 2. The regimen was well tolerated and generated robust, durable immune responses in PWOH and PLWH. Findings support continued evaluation of accelerated vaccine schedules for rapid deployment in populations at immediate risk. Trial registration: NCT02598388 (submitted 14 November 2015). [ABSTRACT FROM AUTHOR]

Background and purpose: Dysphagia is associated with poor outcome, higher mortality, reduced quality of life, and social isolation. We investigate the relationship between swallowing impairment and symptoms of anxiety and depression after ischemic stroke. Methods: Consecutive patients with ischemic stroke participating in the prospective STROKE‐CARD Registry study from 2020 to 2022 were assessed for dysphagia on hospital admission (clinical swallowing assessment) and for persistence until discharge and 3‐month follow‐up (SINGER Independency Index). Anxiety and depression symptoms were recorded using Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS) at 3‐month follow‐up. Results: Of 648 patients, 19.3% had dysphagia on admission, persisting in 14.8% at discharge and 6.8% at 3‐month follow‐up. With the presence or duration of dysphagia (no dysphagia, dysphagia at baseline, at discharge, at 3 months), score (mean ± SD) increased on the BDI (7.9 ± 6.7, 12.5 ± 8.7, 13.5 ± 9.0, 16.5 ± 10.2), HADS‐D (4.4 ± 3.7, 7.1 ± 4.2, 7.7 ± 4.4, 9.8 ± 4.3), and HADS‐A (4.4 ± 3.5, 5.4 ± 3.6, 6.0 ± 3.6, 7.0 ± 3.6). In linear regression analysis adjusting for age, sex, diabetes, dementia, and either functional disability or stroke severity, BDI and HADS‐D scores were significantly higher in patients with dysphagia across all points in time (admission, discharge, 3‐month follow‐up). An independent association with HADS‐A scores was only evident in patients with persisting dysphagia after 3 months. Patients with dysphagia were more likely to receive antidepressants, antipsychotics, or benzodiazepines at discharge and 3‐month follow‐up. Conclusions: Dysphagia after stroke is common and severely affects psychosocial functioning of individuals. Our results highlight swallowing impairment as an independent predictor for poststroke depressive and, to a lesser extent, anxiety symptoms. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate whether headache exacerbation associated with IV dihydroergotamine (DHE) infusion predicts medium-term headache outcome in patients with chronic migraine.MethodsThis was a retrospective chart review study of the UCSF Headache Center's use of IV DHE for chronic migraine from 2008 to 2012. Medium-term headache outcome was assessed at 6-week follow-up. Univariate and multivariate logistic regression models were used to assess for predictors of outcome.ResultsPatients with chronic migraine (n = 274) were treated with a course of IV DHE. Of 214 with 6-week follow-up, 78% had medium-term headache benefit. In a univariate logistic regression model, headache exacerbation with DHE was associated with lower odds of a positive medium-term headache outcome (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.20-0.91). However, in the multivariate logistic regression model, headache exacerbation was no longer an independent predictor of treatment outcome (OR 0.65, 95% CI 0.28-1.51). Factors that independently predicted outcome were nausea (OR 0.12, 95% CI 0.02-1.00, p = 0.05), age (OR 1.68 for each decade increase in age, 95% CI 1.24-2.28), and medication overuse (OR 0.42, 95% CI 0.18-0.97).ConclusionsAfter controlling for nausea and other factors, headache exacerbation with DHE infusions is not an independent predictor of poor headache outcome and clinicians should not interpret its presence as a reason to stop treatment. The focus of management should be on controlling nausea as it is the most important modifiable factor in achieving a good headache outcome with an inpatient course of IV DHE for chronic migraine.

Context.--Northwell Health Laboratories were established in 1997, serving the Northwell Health system. In 2008, the health system considered minority entry into a joint venture with a commercial laboratory. Based on arguments made by Northwell laboratory leadership, the decision was made to retain full ownership of the laboratory. Objective.--To evaluate the 10-year outcomes of the 2008 decision and assess the value of a fully integrated laboratory service line for a regional health network. Design.--Ten-year outcomes were analyzed including financial, volume, and value-based activities. Results.--First, a fully integrated laboratory service line was created, with unified medical and managerial leadership. Second, Core Laboratory volumes and revenues grew at annualized rates of 4.5% and 16.0%, respectively. Third, hospital-based laboratory costs were held either constant, or grew in accordance with strategic clinical programs. Fourth, laboratory services were able to provide leadership in innovative system clinical programming and value-based payment programs. Fifth, the laboratories became a regional asset, forming a joint venture affiliation with New York City Health + Hospitals, and supporting distressed hospitals in Brooklyn, New York. Lastly, Northwell Health Laboratories have become a reputational asset through leadership in 2 consortia: The Compass Group and Project Santa Fe. Conclusions.--The 10-year outcomes have exceeded projections made in 2008, validating the decision to retain the laboratories as a wholly owned system asset. The laboratories are now well positioned for leading innovation in patient care and for helping to drive a favorable posture for the health system under new payment models for health care. doi: 10.5858/arpa.2018-0569-SA, The Northwell Health Laboratories (Lake Success, New York) were established as an in-system Core Laboratory in 1997, for achievement of higher performance and cost efficiencies of the then 8-hospital Northwell [...]