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Introduction: HIV-exposed uninfected (HEU) infants exhibit elevated proinflammatory biomarkers that persist after birth. However, comprehensive assessments of bioprofiles associated with immune regulation and development in pregnant women with HIV (PWH) and HEU infants has not been performed. Maternal immunity in PWH may be imprinted on their HEU newborns, altering immune bioprofiles during early immune development. Methods: Cryopreserved paired plasma samples from 46 HEU infants and their mothers enrolled in PACTG 316, a clinical trial to prevent perinatal HIV-1 transmission were analyzed. PWH received antiretrovirals (ARV) and had either fully suppressed or unsuppressed viral replication. Maternal blood samples obtained during labor and infant samples at birth and 6 months were measured for 21 biomarkers associated with germinal centers (GC), macrophage activation, T-cell activation, interferon gamma (IFN-g)-inducible chemokines, and immune regulatory cytokines using Mesoscale assays. Pregnant women without HIV (PWOH) and their HIV unexposed uninfected (HUU) newborns and non-pregnant women without HIV (NPWOH) served as reference groups. Linear regression analysis fitted for comparison among groups and adjusted for covariant(s) along with principal component analysis performed to assess differences among groups. Results: Compared with NPWOH, PWOH displayed higher levels of GC, macrophage, and regulatory biomarkers. PWH compared to PWOH displayed elevated GC, T cell activation, and IFN-γ-inducible chemokines biomarkers at delivery. Similar to their mothers, HEU infants had elevated GC, macrophage, and IFN-γ-inducible chemokines, as well as elevated anti-inflammatory cytokines, IL-10 and IL-1RA. Across all mother/newborn dyads, multiple biomarkers positively correlated, providing further evidence that maternal inflammation imprints on newborn bioprofiles. By 6 months, many HEU biomarkers normalized to levels similar to HUU infants, but some GC and inflammatory biomarkers remained perturbed. Bioprofiles in PWH and HEU infants were similar regardless of the extent of maternal viral suppression by ARV. Conclusions: GC immune pathways are perturbed in HEU newborns, but immune regulatory responses down regulate inflammation during early infancy, indicating a transient inflammatory effect. However, several GC biomarkers that may alter immune development remain perturbed. [ABSTRACT FROM AUTHOR]

Introduction: Factors influencing vaccine immune priming in the first year of life involve both innate and adaptive immunity but there are gaps in understanding how these factors sustain vaccine antibody levels in healthy infants. The hypothesis was that bioprofiles associated with B cell survival best predict sustained vaccine IgG levels at one year. Methods: Longitudinal study of plasma bioprofiles in 82 term, healthy infants, who received standard recommended immunizations in the United States, with changes in 15 plasma biomarker concentrations and B cell subsets associated with germinal center development monitored at birth, soon after completion of the initial vaccine series at 6 months, and prior to the 12-month vaccinations. Post vaccination antibody IgG levels to Bordetella pertussis, tetanus toxoid, and conjugated Haemophilus influenzae type B (HiB) were outcome measures. Results: Using a least absolute shrinkage and selection operator (lasso) regression model, cord blood (CB) plasma IL-2, IL-17A, IL-31, and soluble CD14 (sCD14) were positively associated with pertussis IgG levels at 12 months, while CB plasma concentrations of APRIL and IL-33 were negatively associated. In contrast, CB concentrations of sCD14 and APRIL were positively associated with sustained tetanus IgG levels. A separate cross-sectional analysis of 18 mother/newborn pairs indicated that CB biomarkers were not due to transplacental transfer, but rather due to immune activation at the fetal/maternal interface. Elevated percentages of cord blood switched memory B cells were positively associated with 12-month HiB IgG levels. BAFF concentrations at 6 and 12 months were positively associated with pertussis and HiB IgG levels respectively. Discussion: Sustained B cell immunity is highly influenced by early life immune dynamics beginning prior to birth. The findings provide important insights into how germinal center development shapes vaccine responses in healthy infants and provide a foundation for studies of conditions that impair infant immune development. [ABSTRACT FROM AUTHOR]

Antagonism of the neonatal Fc receptor (FcRn) by efgartigimod has been studied in several autoimmune diseases mediated by immunoglobulin G (IgG) as a therapeutic approach to remove pathogenic IgGs. Whereas reduction of pathogenic titres has demonstrated efficacy in multiple autoimmune diseases, reducing total IgG could potentially increase infection risk in patients receiving FcRn antagonists. The objective of this study was to analyse the effect of FcRn antagonism with efgartigimod on existing protective antibody titres and the ability to mount an immune response after vaccine challenge. Serum levels of total IgG and protective antibodies against tetanus toxoid (TT), varicella zoster virus (VZV), and pneumococcal capsular polysaccharide (PCP) were measured in all patients enrolled in an open-label trial of efgartigimod for the treatment of pemphigus. Vaccine specific-responses were assessed by measuring changes in IgG titres in patients with generalised myasthenia gravis (gMG) who were treated with efgartigimod and who received influenza, pneumococcal, or coronavirus disease 2019 (COVID-19) vaccines during participation in the double-blind trial ADAPT or open-label extension, ADAPT+ (n = 17). FcRn antagonism reduced levels of protective anti-TT, anti-VZV, and anti-PCP antibodies and total IgG to a similar extent; anti-TT and anti-VZV titres remained above minimally protective thresholds for the majority of patients, (10/12) 83% and (14/15) 93% respectively. Protective antibodies returned to baseline values upon treatment cessation. Antigen-specific IgG responses to influenza, pneumococcal, and COVID-19 immunisation were detected in patients with gMG who received these vaccines while undergoing therapy with efgartigimod. In conclusion, FcRn antagonism with efgartigimod did not hamper generation of IgG responses but did transiently reduce IgG titres of all specificities. [ABSTRACT FROM AUTHOR]

Objective. - To determine if corticosteroids administered in addition to antimicrobials improve survival in children with acquired immunodeficiency syndrome and severe Pneumocystis carinii pneumonia (PCP). Design. - Before-after, nonrandomized, case-comparison study. Setting. - Pediatric intensive care unit of a tertiary care teaching hospital in Florida. Participants. - Eleven children infected with the human immunodeficiency virus (HIV) with confirmed PCP. Selection Procedure. - Infants with HIV infection and acute respiratory failure due to PCP were studied sequentially. Intervention. - The first seven infants were treated with antimicrobials alone while the next four received a 2-week course of methylprednisolone sodium succinate in addition to antimicrobials. Measurements and Results. - The two groups were similar with respect to age, route of HIV infection, stage of HIV disease, CD4 T-cell count, antiretroviral therapy, and respiratory parameters at intubation. All children treated with antimicrobials alone died while receiving mechanical ventilation. Survival of the children who received corticosteroid therapy was significantly improved (P

Abstract Background Deep sequencing provides the basis for analysis of biodiversity of taxonomically similar organisms in an environment. While extensively applied to microbiome studies, population genetics studies of viruses are limited. To define the scope of HIV-1 population biodiversity within infected individuals, a suite of phylogenetic and population genetic algorithms was applied to HIV-1 envelope hypervariable domain 3 (Env V3) within peripheral blood mononuclear cells from a group of perinatally HIV-1 subtype B infected, therapy-naïve children. Results Biodiversity of HIV-1 Env V3 quasispecies ranged from about 70 to 270 unique sequence clusters across individuals. Viral population structure was organized into a limited number of clusters that included the dominant variants combined with multiple clusters of low frequency variants. Next generation viral quasispecies evolved from low frequency variants at earlier time points through multiple non-synonymous changes in lineages within the evolutionary landscape. Minor V3 variants detected as long as four years after infection co-localized in phylogenetic reconstructions with early transmitting viruses or with subsequent plasma virus circulating two years later. Conclusions Deep sequencing defines HIV-1 population complexity and structure, reveals the ebb and flow of dominant and rare viral variants in the host ecosystem, and identifies an evolutionary record of low-frequency cell-associated viral V3 variants that persist for years. Bioinformatics pipeline developed for HIV-1 can be applied for biodiversity studies of virome populations in human, animal, or plant ecosystems.

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part via promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity via neighboring GC-Tfh cells. [ABSTRACT FROM AUTHOR]

Expression of tissue-restricted antigens (TRAs) in thymic epithelial cells (TECs) ensures negative selection of highly self-reactive T cells to establish central tolerance. Whether some of these TRAs could exert their canonical biological functions to shape thymic environment to regulate T cell development is unclear. Analyses of publicly available databases have revealed expression of transcripts at various levels of many cytokines and cytokine receptors such as IL-15, IL-15Rα, IL-13, and IL-23a in both human and mouse TECs. Ablation of either IL-15 or IL-15Rα in TECs selectively impairs type 1 innate like T cell, such as i NKT1 and γδT1 cell, development in the thymus, indicating that TECs not only serve as an important source of IL-15 but also trans-present IL-15 to ensure type 1 innate like T cell development. Because type 1 innate like T cells are proinflammatory, our data suggest the possibility that TEC may intrinsically control thymic inflammatory innate like T cells to influence thymic environment. [ABSTRACT FROM AUTHOR]

Abstract Background Co-infections of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (M. Tb) are steadily increasing and represent a major health crisis in many developing countries. Both pathogens individually stimulate tumor necrosis factor-alpha (TNF) release from infected cells and TNF, in turn, enhances the replication of each. A recent report on a Phase I clinical trial suggested that etanercept (soluble TNF receptor) might be beneficial in treating HIV/M. Tb co-infected patients. We sought to determine if a small molecule inhibitor of TNF synthesis and activity could block replication of either organism and thus be a potential adjunct to existing drugs targeting these agents. Results LMP-420, a novel anti-inflammatory agent that inhibits TNF, was tested for HIV-1 inhibition both alone and in combination with AZT (3' -azido-3-deoxythymidine). LMP-420 alone was tested against M. Tb. HIV-1 infected human peripheral blood mononuclear cells (PBMC) or M. Tb-infected human alveolar macrophages (AM) were treated with a single dose of LMP-420 and viral or bacterial replication determined after 7 or 5 days respectively. Viral replication was determined from supernatant p24 levels measured by ELISA. M. Tb replication was determined by bacterial culture of macrophage lysates. LMP-420 alone inhibited HIV replication over 7 days with an IC50 of ~300 nM. Combination of LMP-420 with AZT doubled the level of HIV inhibition observed with AZT alone. LMP-420 alone inhibited the replication of virulent M. Tb by >80%, more than that observed with anti-TNF antibody alone. Conclusion Inhibition of TNF with inexpensive, small-molecule, orally-active drugs may represent a useful strategy for enhancing the activity of currently-available antiviral and anti-M. Tb agents, particularly in those areas where co-infections with these pathogens act to synergistically enhance each other.

Diacylglycerol kinases (DGKs) play important roles in restraining diacylglycerol (DAG)‐mediated signaling. Within the DGK family, the ζ isoform appears to be the most important isoform in T cells for controlling their development and function. DGKζ has been demonstrated to regulate T cell maturation, activation, anergy, effector/memory differentiation, defense against microbial infection, and antitumor immunity. Given its critical functions, DGKζ function should be tightly regulated to ensure proper signal transduction; however, mechanisms that control DGKζ function are still poorly understood. We report here that DGKζ dynamically translocates from the cytosol into the nuclei in T cells after TCR stimulation. In mice, DGKζ mutant defective in nuclear localization displayed enhanced ability to inhibit TCR‐induced DAG‐mediated signaling in primary T cells, maturation of conventional αβT and iNKT cells, and activation of peripheral T cells compared with WT DGKζ. Our study reveals for the first time nuclear sequestration of DGKζ as a negative control mechanism to spatially restrain it from terminating DAG mediated signaling in T cells. Our data suggest that manipulation of DGKζ nucleus‐cytosol shuttling as a novel strategy to modulate DGKζ activity and immune responses for treatment of autoimmune diseases and cancer. [ABSTRACT FROM AUTHOR]

Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines. [ABSTRACT FROM AUTHOR]

Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26–39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1–11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11–55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population. [ABSTRACT FROM AUTHOR]

Both HIV infection and tenofovir disoproxil fumarate (TDF) treatment adversely impact bone metabolism and may lead to osteopenia, which has critical implications for youth with HIV (YWH). This study evaluates changes in the biomarkers of bone metabolism and inflammation among YWH receiving initial treatment with TDF- and non-TDF-containing antiretroviral therapies (ARTs). YWH [n = 23, median age 21 years (range 18–24), 87% male, 61% African American] were assessed for inflammatory and bone metabolism biomarkers at enrollment, after 48 weeks of TDF-containing ART, and 96 weeks of ART without TDF with continued viral suppression. Spearman's rank correlation evaluated biomarker associations. Bone alkaline phosphatase, parathyroid hormone, and osteopontin increased after TDF treatment. All fell after TDF was discontinued. Levels of RANKL and osteoprotegerin did not change throughout the study. There was little correlation between biomarkers of bone metabolism and either macrophage or lymphocyte activation at any time point. Our results establish baseline associations between bone metabolism and immune biomarkers for this population, and find that before CD4 T cell decline chronic inflammation does not perturb biomarkers of bone metabolism among YWH. The adverse effects of TDF on bone health may be marginal for YWH at the early stages of disease. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To define inflammatory pathways in youth living with HIV infection (YLWH), assessments of biomarkers associated with lymphocyte and macrophage activation, vascular injury, or bone metabolism were performed in YLWH in comparison with healthy controls (HC). Design:  Longitudinal multicenter study comparing biomarkers in YLWH suppressed on antiretroviral therapy (ART), those with ongoing viral replication, and HC were compared using single blood samples obtained at end of study. Methods:  Twenty‐three plasma proteins were measured by ELISA or multiplex assays. Principal component analysis (PCA) was used to define contributions of individual biomarkers to define outcome groups. Results:  The study cohort included 129 predominantly African American, male participants, 21–25 years old at entry. Nine biomarkers of lymphocyte and macrophage activation and cardiovascular injury differed between HC and YLWH. Significant positive correlations were identified between lymphocyte and macrophage activation biomarkers among HC and YLWH. Correlations distinct to YLWH were predominantly between biomarkers of macrophage and vascular inflammation. PCA of outcome groups showed HC and suppressed YLWH clustering together for lymphocyte activation biomarkers, whereas macrophage activation markers showed all YLWH clustering distinct from HC. Cardiovascular biomarkers were indistinguishable across groups. Averaged variable importance projection to assess single biomarkers that maximally contribute to discriminate among outcome groups identified soluble CD27, CD14, and CD163 as the 3 most important with TNFα and LPS also highly relevant in providing separation. Conclusions:  Soluble inflammatory and lymphocyte biomarkers sufficiently distinguish YLWH from HC. Persistent macrophage activation biomarkers may provide a means to monitor consequences of HIV infection in fully suppressed YLWH. [ABSTRACT FROM AUTHOR]

Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFNγ-priming, HIV-1 primes macrophages, resulting in hyperresponsiveness to subsequent toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1 priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFNγ or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFNγ-primed cells that was further modulated by the addition of lipopolysaccharide (LPS). HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFNγ ( r = .679, p = .003). Similar to IFNγ, HIV-1 enhanced TLR ligand-induced tumor necrosis factor (TNF) protein expression and release. Increased TNF production was limited to productively infected cells. Specific signal transducer and activator of transcription (STAT)1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFNγ-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication. [ABSTRACT FROM AUTHOR]