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Objectives: The InVITE study, starting in August 2021, was designed to examine the immunogenicity of different vaccine regimens in several countries including the Democratic Republic of Congo, Guinea, Liberia, and Mali. Prevaccination baseline samples were used to obtain estimates of previous SARS-CoV-2 infection in the study population. Methods: Adult participants were enrolled upon receipt of their initial COVID-19 vaccine from August 2021 to June 2022. Demographic and comorbidity data were collected at the time of baseline sample collection. SARS-CoV-2 serum anti-Spike and anti-Nucleocapsid antibody levels were measured. Results: Samples tested included 1016, 375, 663, and 776, from DRC, Guinea, Liberia, and Mali, respectively. Only 0.8% of participants reported a prior positive SARS-CoV-2 test, while 83% and 68% had anti-Spike and anti-Nucleocapsid antibodies, respectively. Conclusions: Overall SARS-CoV-2 seroprevalence was 86% over the accrual period, suggesting a high prevalence of SARS-CoV-2 infection. Low rates of prior positive test results may be explained by asymptomatic infections, limited access to SARS-CoV-2 test kits and health care, and inadequate surveillance. These seroprevalence rates are from a convenience sample and may not be representative of the population in general, underscoring the need for timely, well-conducted surveillance as part of global pandemic preparedness.

[This corrects the article DOI: 10.1371/journal.pone.0273914.].

Summary: Background: After initiating antiretroviral therapy (ART), approximately 25% of people with HIV (PWH) may develop Immune Reconstitution Inflammatory Syndrome (IRIS), which is associated with increased morbidity and mortality. Several reports have demonstrated that low haemoglobin (Hb) levels are a risk factor for IRIS. To what extent the severity of anaemia contributes to the risk of IRIS and/or death is still insufficiently explored. Methods: We investigated both the presence and severity of anaemia in PWH in a multinational cohort of ART-na..ve patients. A large panel of plasma biomarkers was measured pre-ART and patients were followed up for 6 months. IRIS or deaths during this period were considered as outcomes. We performed multidimensional analyses, logistic regression, and survival curves to delineate associations. Findings: Patients with severe anaemia (SA) presented a distinct systemic inflammatory profile, characterized by higher TNF, IL-6, and IL-27 levels. SA was independently associated with IRIS, with a higher risk of both early IRIS onset and death. Among IRIS patients, those with SA had a higher risk of mycobacterial IRIS. Interpretation: PWH with SA display a more pronounced inflammatory profile, with an elevated risk of developing IRIS earlier and a statistically significant higher risk of death. Funding: Intramural Research Program of National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH). Coordena...·o de Aperfei..oamento de Pessoal de N.ível Superior (Finance code: 001) and the Conselho Nacional de Desenvolvimento Cient.ífico e Tecnol..gico (CNPq), Brazil.

People with HIV (PWH) are at increased risk of developing active tuberculosis (TB), and anemia is a common complication in both conditions. Anemia in TB patients has been linked to immune activation, levels of inflammatory biomarkers in blood, and risk for HIV disease progression and death. In this study we show that anemia was associated with a more pronounced inflammatory profile in HIV-TB coinfected persons in a cohort of 159 individuals with advanced HIV disease (CD4 count < 100 cells/µL) recruited as part of a randomized clinical trial (NCT00988780). A panel of plasma biomarkers was assessed on plasma obtained prior to combination antiretroviral therapy (cART) initiation. We performed a series of multidimensional analyses including clinical variables and concentrations of inflammatory biomarkers to profile systemic inflammation of PWH with and without anemia. We observed that TB participants presented with moderately lower levels of hemoglobin than non-TB participants. These participants also presented a higher Degree of Inflammatory Perturbation (DIP) score, related to increased levels of IFN-γ and TNF. The DIP was associated with TB coinfection and anemia before cART initiation. Future mechanistic studies are warranted to assess the determinants of such associations and the implications on treatment outcomes.

Abstract Aims Efforts to improve access to antiretroviral therapy (ART) have shifted morbidity and mortality among persons living with HIV (PLWH) from AIDS to non‐communicable diseases, such as cardiovascular disease (CVD). However, contemporary data on CVD among PLWH in sub‐Saharan Africa in the current ART era are lacking. The aim of this study was to assess the burden of cardiac stress among PLWH in South Africa via measurement of N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP). Methods and results NT‐proBNP was measured at baseline in 224 PLWH enrolled in a sub‐study of a tuberculosis vaccine trial in Khayelitsha township near Cape Town, South Africa. Thresholds were applied at the assay's limit of detection (≥137 pg/mL) and a level indicative of symptomatic heart failure in the acute setting (>300 pg/mL). Mean (SD) age of participants was 39 (6) years, 86% were female, and 19% were hypertensive. Mean (SD) duration of HIV diagnosis was 8.3 (3.9) years and CD4 + count was 673 (267) with 79% prescribed ART for a duration of 5.6 (2.7) years. Thirty‐one percent of participants had NT‐proBNP > 300 pg/mL. Elevated vs. undetectable NT‐proBNP level was associated with older age (P = 0.04), no ART (P = 0.03), and higher plasma tumour necrosis factor‐α (P = 0.01). Conclusions Among South African PLWH largely free of known CVD and on ART with high CD4 + counts and few comorbidities, we observed a high proportion with elevated NT‐proBNP levels, suggesting the burden of cardiac stress in this population may be high. This observation underscores the need for more in‐depth research, including the current effect of HIV on heart failure risk among a growing ART‐treated population in sub‐Saharan Africa.

The coronavirus disease-2019 (COVID-19) caused by the SARS-CoV-2 virus may vary from asymptomatic to severe infection with multi-organ failure and death. Increased levels of circulating complement biomarkers have been implicated in COVID-19-related hyperinflammation and coagulopathy. We characterized systemic complement activation at a cellular level in 49-patients with COVID-19. We found increases of the classical complement sentinel C1q and the downstream C3 component on circulating blood monocytes from COVID-19 patients when compared to healthy controls (HCs). Interestingly, the cell surface-bound complement inhibitor CD55 was also upregulated in COVID-19 patient monocytes in comparison with HC cells. Monocyte membrane-bound C1q, C3 and CD55 levels were associated with plasma inflammatory markers such as CRP and serum amyloid A during acute infection. Membrane-bounds C1q and C3 remained elevated even after a short recovery period. These results highlight systemic monocyte-associated complement activation over a broad range of COVID-19 disease severities, with a compensatory upregulation of CD55. Further evaluation of complement and its interaction with myeloid cells at the membrane level could improve understanding of its role in COVID-19 pathogenesis.

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16− monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1β secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.

In response to the COVID-19 pandemic, COVID-19 vaccines have been developed, and the World Health Oraganization (WHO) has granted emergency use listing to multiple vaccines. Studies of vaccine immunogenicity data from implementing COVID-19 vaccines by national immunization programs in single studies spanning multiple countries and continents are limited but critically needed to answer public health questions on vaccines, such as comparing immune responses to different vaccines and among different populations.

Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.

Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory complication associated with an underlying opportunistic infection that can be observed in HIV-infected individuals shortly after the initiation of antiretroviral therapy, despite successful suppression of HIV viral load and CD4+ T cell recovery. Better understanding of IRIS pathogenesis would allow for targeted prevention and therapeutic approaches. In this study, we sought to evaluate the metabolic perturbations in IRIS across longitudinal time points using an unbiased plasma metabolomics approach as well as integrated analyses to include plasma inflammatory biomarker profile and whole blood transcriptome. We found that many lipid and amino acid metabolites differentiated IRIS from non-IRIS conditions prior to antiretroviral therapy and during the IRIS event, implicating the association between oxidative stress, tryptophan pathway, and lipid mediated signaling and the development of IRIS. Lipid and amino acid metabolic pathways also significantly correlated with inflammatory biomarkers such as IL-12p70 and IL-8 at the IRIS event, indicating the role of cellular metabolism on cell type specific immune activation during the IRIS episode and in turn the impact of immune activation on cellular metabolism. In conclusion, we defined the metabolic profile of IRIS and revealed that perturbations in metabolism may predispose HIV-infected individuals to IRIS development and contribute to the inflammatory manifestations during the IRIS event. Furthermore, our findings expanded our current understanding IRIS pathogenesis and highlighted the significance of lipid and amino acid metabolism in inflammatory complications.

Inflammasome-derived cytokines, IL-1β and IL-18, and complement cascade have been independently implicated in the pathogenesis of tuberculosis (TB)-immune reconstitution inflammatory syndrome (TB-IRIS), a complication affecting HIV+ individuals starting antiretroviral therapy (ART). Although sublytic deposition of the membrane attack complex (MAC) has been shown to promote NLRP3 inflammasome activation, it is unknown whether these pathways may cooperatively contribute to TB-IRIS. To evaluate the activation of inflammasome, peripheral blood mononuclear cells (PBMCs) from HIV-TB co-infected patients prior to ART and at the IRIS or equivalent timepoint were incubated with a probe used to assess active caspase-1/4/5 followed by screening of ASC (apoptosis-associated speck-like protein containing a CARD domain) specks as a readout of inflammasome activation by imaging flow cytometry. We found higher numbers of monocytes showing spontaneous caspase-1/4/5+ASC-speck formation in TB-IRIS compared to TB non-IRIS patients. Moreover, numbers of caspase-1/4/5+ASC-speck+ monocytes positively correlated with IL-1β/IL-18 plasma levels. Besides increased systemic levels of C1q and C5a, TB-IRIS patients also showed elevated C1q and C3 deposition on monocyte cell surface, suggesting aberrant classical complement activation. A clustering tSNE analysis revealed TB-IRIS patients are enriched in a CD14highCD16- monocyte population that undergoes MAC deposition and caspase-1/4/5 activation compared to TB non-IRIS patients, suggesting complement-associated inflammasome activation during IRIS events. Accordingly, PBMCs from patients were more sensitive to ex-vivo complement-mediated IL-1β secretion than healthy control cells in a NLRP3-dependent manner. Therefore, our data suggest complement-associated inflammasome activation may fuel the dysregulated TB-IRIS systemic inflammatory cascade and targeting this pathway may represent a novel therapeutic approach for IRIS or related inflammatory syndromes.

Background: In HIV infection, lymphoid tissue is disrupted by fibrosis. Angiotensin converting enzyme inhibitors have anti-fibrotic properties. We completed a pilot study to assess whether the addition of lisinopril to antiretroviral therapy (ART) reverses fibrosis of gut tissue, and whether this leads to reduction of HIV RNA and DNA levels. Methods: Thirty HIV-infected individuals on ART were randomized to lisinopril at 20mg daily or matching placebo for 24 weeks. All participants underwent rectal biopsies prior to starting the study drug and at 22 weeks, and there were regular blood draws. The primary end point was the change in HIV RNA and DNA levels in rectal tissue. Secondary outcomes included the change in 1) HIV levels in blood; 2) Gag-specific T-cell responses; 3) levels of T-cell activation; and 4) collagen deposition. Results: The addition of lisinopril did not have a significant effect on the levels of HIV RNA or DNA in gut tissue or blood, Gag-specific responses, or levels of T-cell activation. Lisinopril also did not have a significant impact on lymphoid fibrosis in the rectum, as assessed by quantitative histology or heavy water labeling. Conclusions: Treatment with lisinopril for 24 weeks in HIV-infected adults did not have an effect on lymphoid fibrosis, immune activation, or gut tissue viral reservoirs. Further study is needed to see if other anti-fibrotic agents may be useful in reversing lymphoid fibrosis and reducing HIV levels. Clinical Trials Registration: NCT01535235

Autoimmune lymphoproliferative syndrome (ALPS) is caused by germline or somatic loss of function FAS mutations resulting in impaired apoptosis and consequent expansion of T-lymphocytes causing organomegaly and autoimmune anemia, neutropenia and thrombocytopenia. Herein, we report on a case of disseminated varicella zoster infection after post-partum vaccination in a patient found to have CD4 lymphopenia and eventually diagnosed with ALPS caused by a novel germline missense mutation in FAS death-domain. A subsequent retrospective analysis of 169 patients of the NIH ALPS-FAS cohort, revealed that CD4-T-cells lymphopenia (< 300 cells/μl) may occur in 5% of ALPS-FAS patients irrespectively of the underlying genetic defect, organomegaly or immunosuppressive treatment. Although immunophenotyping did not show depletion of specific CD4-T-cells subpopulations, CD4-lymphopenic ALPS-FAS subjects had an expansion of a subset of circulating T-follicular-helper (cTfh) cells, associated with autoantibody production (CCR7lowPD-1high). Furthermore, autoantibodies binding on CD4-T-cells were detected in 50% of the CD4-lymphopenic ALPS-FAS patients and caused cytotoxicity in a natural killer (NK)-mediated antibody-dependent-cellular cytotoxicity assay. Such autoantibodies can therefore be associated with CD4-T-cell death, impaired activation induced proliferation or impaired trafficking. The expansion of autoreactive T-cells in ALPS-FAS is known to be associated with autoimmune clinical manifestations, however our study reveals that ALPS-FAS can also be associated with a paradoxical depletion of CD4-T-cells due to the presence of autoantibodies on the surface of CD4-T-cells which can in turn result in increased susceptibility to opportunistic infections. These novel findings have implications for the diagnosis, clinical monitoring, and management of patients with ALPS-FAS.

Background: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of sa:country of residence on these biomarkers is unknown and was investigated in persons at similar stages of HIV infection. Methods: Cryopreserved plasma specimens were analysed from 267 ART-naive patients with CD4 cell counts

To determine the immunological profile most important for IRIS prediction, we evaluated 20 baseline plasma biomarkers in Acquired Immunodeficiency Syndrome (AIDS) patients initiating antiretroviral therapy (ART). Patients were enrolled in a randomized, placebo-controlled ART initiation trial in South Africa and Mexico to test whether maraviroc could prevent IRIS. Participants were classified prospectively as having IRIS within 6 months of ART initiation. Twenty plasma biomarkers were measured at study enrollment for 267 participants. Biomarkers were tested for predicting IRIS with adjustment for covariates chosen through forward stepwise selection. Sixty-two participants developed IRIS and of these 19 were tuberculosis (TB)-IRIS. Baseline levels of vitamin D and higher d-dimer, interferon gamma (IFNγ), and sCD14 were independently associated with risk of IRIS in multivariate analyses. TB-IRIS cases exhibited a distinct biosignature from IRIS related to other pathogens, with increased levels of C-reactive protein (CRP), sCD14, IFNγ, and lower levels of Hb that could be captured by a composite risk score. Elevated markers of Type 1 T helper (Th1) response, monocyte activation, coagulation and low vitamin D were independently associated with IRIS risk. Interventions that decrease immune activation and increase vitamin D levels warrant further study.

Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies.Among patients with RT-PCR-confirmed influenza A(H1N1)pdm09 virus infection, odds ratios (ORs) estimated by logistic regression were used to summarize the associations of biomarkers measured at enrollment with worsened disease outcome or death after 14 days of follow-up for those seeking outpatient care (FLU 002) or after 60 days for those hospitalized with influenza complications (FLU 003). Biomarkers that were significantly associated with progression in both studies (p

Two studies were conducted to evaluate interventions, based upon the extended contact hypothesis and multiple classification skills training, which aimed to promote children's positive intergroup attitudes towards two stigmatized groups. Study 1 tested whether extended contact and multiple classification skills training changed out-group attitudes towards the disabled among 6-9 year-old children. Out-group attitudes were significantly more positive only in the extended contact condition compared to the control. Study 2 involved four conditions: control, extended contact, modified multiple classification skills training and a combination of both interventions. Again, only the 6-11 year-old children who experienced the extended contact interventions (extended contact and combined) showed significantly more positive attitudes towards the refugee out-group compared to the control. The implications of these findings for the development of prejudice-reduction strategies in children will be discussed. [ABSTRACT FROM AUTHOR]