Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis.

Objectives: We aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system.

Design: In two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH.

Mediators of monocyte chemotaxis and matrix remodeling are associated with mortality and pulmonary fibroproliferation in patients with severe COVID-19.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation.

PD-L1 and PD-1 Are Associated with Clinical Outcomes and Alveolar Immune Cell Activation in Acute Respiratory Distress Syndrome.

The relationship between the PD-L1 (Programmed Death-Ligand 1)/PD-1 pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 [ = 59] and ARDS2 [ = 78]) or plasma samples alone (ARDS3 [ = 149]) collected from subjects with ARDS and tested for associations with mortality using multiple regression.

Phase 2, randomized, double-blind, placebo-controlled multi-center trial of the clinical and biological effects of anti-CD14 treatment in hospitalized patients with COVID-19 pneumonia.

Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target.

Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo.

Mediators of monocyte chemotaxis and matrix remodeling are associated with the development of fibrosis in patients with COVID-19.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. This has been described in patients with COVID-19 pneumonia, but the underlying mechanisms have not been completely defined. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop radiographic fibrosis.

Cross-reactive and mono-reactive SARS-CoV-2 CD4+ T cells in prepandemic and COVID-19 convalescent individuals.

Class II tetramer reagents for eleven common DR alleles and a DP allele prevalent in the world population were used to identify SARS-CoV-2 CD4+ T cell epitopes. A total of 112, 28 and 42 epitopes specific for Spike, Membrane and Nucleocapsid, respectively, with defined HLA-restriction were identified. Direct ex vivo staining of PBMC with tetramer reagents was used to define immunodominant and subdominant T cell epitopes and estimate the frequencies of these T cells in SARS-CoV-2 exposed and naïve individuals.

Endomembrane targeting of human OAS1 p46 augments antiviral activity.

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication.

Early Prognostic Indicators of Subsequent Hospitalization in Patients with Mild COVID-19.

Comprehensive data on early prognostic indicators in patients with mild COVID-19 remains sparse. In this single center case series, we characterized the initial clinical presentation in 180 patients with mild COVID-19 and defined the earliest predictors of subsequent deterioration and need for hospitalization. Three broad patient phenotypes and four symptom clusters were characterized, differentiated by varying risk for adverse outcomes.

The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity.

BACKGROUNDDespite a rapidly growing body of literature on coronavirus disease 2019 (COVID-19), our understanding of the immune correlates of disease severity, course, and outcome remains poor.METHODSUsing mass cytometry, we assessed the immune landscape in longitudinal whole-blood specimens from 59 patients presenting with acute COVID-19 and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls.

Ontogeny of different subsets of yellow fever virus-specific circulatory CXCR5 CD4 T cells after yellow fever vaccination.

Monitoring the frequency of circulatory CXCR5 (cCXCR5) CD4 T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (T) activity within germinal center. However, cCXCR5 T cells are highly heterogeneous in their expression of ICOS, PD1 and CD38 and the relationship between different cCXCR5 subsets as delineated by these markers remains unclear. We applied class II tetramer reagents and mass cytometry to investigate the ontogeny of different subsets of cCXCR5 T cell following yellow fever immunization.

Acute limb ischemia as sole initial manifestation of SARS-CoV-2 infection.

We present the case of a patient with acute upper limb ischemia as the sole initial manifestation of severe acute respiratory syndrome associated with coronavirus disease 2 infection, without concomitant respiratory symptoms or pneumonia. Viral infection presumably precipitated the patient's thromboembolic event, causing multifocal vascular occlusions. This case illustrates that coronavirus disease-19 must be considered in the differential diagnosis of patients presenting with signs or symptoms of coagulopathy, even in the absence of respiratory symptoms.

Neuroinvasive West Nile Infection Elicits Elevated and Atypically Polarized T Cell Responses That Promote a Pathogenic Outcome.

Most West Nile virus (WNV) infections are asymptomatic, but some lead to neuroinvasive disease with symptoms ranging from disorientation to paralysis and death. Evidence from animal models suggests that neuroinvasive infections may arise as a consequence of impaired immune protection. However, other data suggest that neurologic symptoms may arise as a consequence of immune mediated damage.

Cyclophosphamide Treatment for Acquired Factor VIII Inhibitor in a Patient with AIDS-Associated Progressive Multifocal Leukoencephalopathy.

Acquired hemophilia A (AHA) is a severe bleeding disorder with high mortality rates resulting from the development of autoantibodies to factor VIII (FVIII). Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles, which are frequently severe. They can also develop life-threatening retroperitoneal hematomas and compartment syndromes.

Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins.

Yellow fever virus (YFV) can induce acute, life-threatening disease that is a significant health burden in areas where yellow fever is endemic, but it is preventable through vaccination. The live attenuated 17D YFV strain induces responses characterized by neutralizing antibodies and strong T cell responses. This vaccine provides an excellent model for studying human immunity.

CD4+ T cells recognize unique and conserved 2009 H1N1 influenza hemagglutinin epitopes after natural infection and vaccination.

Influenza A/California/4/2009 (H1N1/09) is a recently emerged influenza virus capable of causing serious illness or death in otherwise healthy individuals. Serious outcomes were most common in young adults and children, suggesting that pre-existing heterologous immunity may influence the severity of infection. Using tetramers, we identified CD4(+) T-cell epitopes within H1N1/09 hemagglutinin (HA) that share extensive homology with seasonal influenza and epitopes that are unique to H1N1/09 HA.

Characterization of Gag and Nef-specific ELISpot-based CTL responses in HIV-1 infected Indian individuals.

Cytotoxic T lymphocyte (CTL) responses to Gag have been most frequently linked to control of viremia whereas CTL responses to Nef have direct relationship with viral load. IFN-gamma ELISpot assay was used to screen CTL responses at single peptide level directed at HIV-1 subtype C Gag and Nef proteins in 30 antiretroviral therapy naive HIV-1 infected Indian individuals. PBMCs from 73.

Generation of HIV-1-specific CD8+ cell responses following allogeneic hematopoietic cell transplantation.

This study tested whether donor-derived HIV-specific immune responses could be detected when viral replication was completely suppressed by the continuous administration of highly active antiretroviral therapy (HAART). A regimen of fludarabine and 200 cGy total body irradiation was followed by infusion of allogeneic donor peripheral blood cells and posttransplantation cyclosporine and mycophenolate mofetil. Viral load, lymphocyte counts, and HIV-1-specific CD8(+) cell immune responses were compared before and after hematopoietic cell transplantation (HCT).

Towards prediction of degenerate CTL epitope recognition.

The cellular immune system is characterized by flexibility with respect to epitope recognition at the level of peptide binding to HLA molecules and HLA-peptide complexes to T-cell receptors (TCRs). For epitopes recognized by cytotoxic T-lymphocytes (CTLs), amino acid substitutions at different positions have varying impact on recognition. By analyzing the frequencies of specific amino acid substitutions at each position in conjunction with HLA-peptide binding and immune-response data, we have developed new methods to predict cross-reactive recognition of epitope variants by CTLs.

Enhanced detection of human immunodeficiency virus type 1 (HIV-1) Nef-specific T cells recognizing multiple variants in early HIV-1 infection.

A human immunodeficiency virus (HIV)-preventive vaccine will likely need to induce broad immunity that can recognize antigens expressed within circulating strains. To understand the potentially relevant responses that T-cell based vaccines should elicit, we examined the ability of T cells from early infected persons to recognize a broad spectrum of potential T-cell epitopes (PTE) expressed by the products encoded by the HIV type 1 (HIV-1) nef gene, which is commonly included in candidate vaccines. T cells were evaluated for gamma interferon (IFN-gamma) secretion using two peptide panels: subtype B consensus (CON) peptides and a novel peptide panel providing 70% coverage of PTE in subtype B HIV-1 Nef.

Comprehensive epitope analysis of cross-clade Gag-specific T-cell responses in individuals with early HIV-1 infection in the US epidemic.

To elucidate the mechanisms underlying cross-clade T-cell reactivity, we evaluated responses to Gag peptides based on clades A, B, C, and M-group sequences at the epitope level by IFN-gamma ELISpot assay in 25 subjects following primary clade B infection. T-cell reactivity to CON (consensus), COT (center of tree), and ANC (most recent common ancestor) B peptides was similar and a high level of cross-reactivity was noted to clade A, C, and M-group peptides. T-cell responses to 15 of the 16 epitopes reacted with at least 1 of the 2 heterologous peptides (A or C or both) and 7 epitopes were invariant across all 3 clades.

Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation.

Dozens of human immunodeficiency virus-type 1 (HIV-1) vaccine candidates specifically designed to elicit cytotoxic T-lymphocyte (CTL) responses have entered the pipeline of clinical trials. Evaluating the immunogenicity and potential efficacy of these HIV-1 vaccine candidates is challenging in the face of the extensive viral genetic diversity of circulating strains. Standardized peptide reagents to define the magnitude and potential breadth of the T-cell response, especially to circulating strains of HIV-1, are needed.

Abacavir hypersensitivity reaction in primary HIV infection.

Objective: To evaluate risk factors associated with the abacavir hypersensitivity reaction during primary HIV infection (PHI).

Design: Acute HIV Infection and Early Disease Research Program protocol (AIEDRP) AI-02-001 provided antiretroviral therapy including abacavir. This retrospective analysis evaluated variables potentially associated with hypersensitivity in the cohort enrolled in AI-02-001 at the University of Washington Primary Infection Clinic.

CD4+ T cell receptor repertoire perturbations in HIV-1 infection: association with plasma viremia and disease progression.

CD4+ T cell depletion and dysfunction are the hallmark of HIV-1 disease. Our primary objectives were to define the diversity of the CD4+ T cell receptor Vbeta (TCRBV) repertoire in subjects with HIV-1 infection by CDR3 (complementarity-determining region) length spectratyping and to determine the correlates of CD4+ repertoire perturbation and its restoration with virus suppression. During primary HIV-1 infection, the proportion of perturbed CD4+ TCRBV subfamilies was significantly greater compared to HIV-1 seronegative subjects (median 48% vs.

Effect of adjunct hydroxyurea on helper T cell immunity in HIV type 1-infected patients with virological suppression.

Hydroxyurea (HU) has preferential activity in virus reservoirs not effectively targeted by current antiretroviral drug regimens, but concern for potential toxicity has precluded its routine use. The effect of adjunct HU on T cell proliferative responses and phenotypic markers was examined in a randomized study of 39 chronically HIV-1-infected patients with virological suppression on potent antiretroviral therapy. While patients in the HU arm showed modest declines in the median CD4(+) T cell counts (total, -151 cells/mm(3); naive, -91 cells/mm(3)), no significant differences were noted in the Candida, HIV-1 p24, and HIV-1 gp160 responses between the treatment arms following 24 weeks of therapy.