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Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.In this Review, Tschöpe and colleagues summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with special focus on virus-induced and virus-associated myocarditis. The authors also identify knowledge gaps, appraise available experimental models and propose future directions for the field.

Mental health and HIV/AIDS are closely interlinked.  Mental disorders, including substance-use disorders, are associated with increased risk of HIV infection and affect adherence to and efficacy of antiretroviral treatments.  Conversely, HIV infection can increase risk for neuropsychiatric complications including stress, mood, and neurocognitive disorders.  This book provides clinicians with a comprehensive evidenced-based and practical approach to the management of patients with HIV infection and co-morbid mental disorders. It provides up-to-date and clear overviews of current clinical issues, as well as the relevant basic science.  Information and data from studies of different HIV groups (eg men who have sex with men) make the text relevant to a broad spectrum of clinicians, including those working with low socioeconomic status groups in high income countries and those working in the developing world. The book uses the popular format of the World Psychiatric Association's Evidence and Experience series.  Review chapters summarize the evidence on the epidemiology, pathogenesis and clinical aspects of mental disorders in HIV,and interventions (both psychotherapy and psychopharmacology including drug-drug interactions).  These are complemented by commentaries addressing particular facets of each topic and providing insight gained from clinical experience.  Psychiatrists, psychologists and all mental health staff working with HIV-infected patients will find this book of great benefit.

Correspondence to Prof An Hendrix, Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent 9000, Belgium; an.hendrix@ugent.be We read with interest recent papers reporting on the impact of gut microbiota on several aspects of health and disease due to altered intestinal permeability resulting in systemic immune activation by pathogen-associated molecular patterns (PAMP), a process termed microbial translocation.1–4 Common to these studies is the analysis of systemic lipopolysaccharide (LPS), the major outer membrane PAMP of Gram-negative bacteria, to quantitatively assess microbial translocation. Online supplementary table 1 summarises individual patient characteristics; 25 donors asymptomatic of intestinal barrier dysfunction (12 healthy volunteers and 13 patients with cancer during chemotherapy without GI side effects suggestive for intestinal mucositis) and 24 patients with clinically well-defined intestinal barrier dysfunction (13 patients with IBD, 5 patients with cancer with radiation or chemotherapy-induced intestinal mucositis and 6 treatment-naive patients with HIV). [...]LPS-positive bacterial EV are present in plasma, are able to induce immune activation and correlate with impaired barrier integrity in patients diagnosed with IBD, HIV and cancer therapy-induced intestinal mucositis (figure 2).

Antiretroviral therapy has largely transformed HIV infection into a chronic disease condition. As such, physicians and other providers caring for individuals living with HIV infection need to be aware of the potential cardiovascular complications of HIV infection and the nuances of how HIV infection increases the risk of cardiovascular diseases, including acute myocardial infarction, stroke, peripheral artery disease, heart failure and sudden cardiac death, as well as how to select available therapies to reduce this risk. In this Review, we discuss the epidemiology and clinical features of cardiovascular disease, with a focus on coronary heart disease, in the setting of HIV infection, which includes a substantially increased risk of myocardial infarction even when the HIV infection is well controlled. We also discuss the mechanisms underlying HIV-associated atherosclerotic cardiovascular disease, such as the high rates of traditional cardiovascular risk factors in patients with HIV infection and HIV-related factors, including the use of antiretroviral therapy and chronic inflammation in the setting of effectively treated HIV infection. Finally, we highlight available therapeutic strategies, as well as approaches under investigation, to reduce the risk of cardiovascular disease and lower inflammation in patients with HIV infection.Antiretroviral therapy has transformed HIV infection into a chronic disease, and cardiovascular diseases are an important health concern in this setting. This Review discusses the clinical features of cardiovascular disease in patients with HIV infection, including the mechanisms underlying HIV-associated atherosclerosis and approaches to reduce the cardiovascular risk.

Graves’ disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism and occurs at all ages but especially in women of reproductive age. Graves’ hyperthyroidism is caused by autoantibodies to the thyroid-stimulating hormone receptor (TSHR) that act as agonists and induce excessive thyroid hormone secretion, releasing the thyroid gland from pituitary control. TSHR autoantibodies also underlie Graves’ orbitopathy (GO) and pretibial myxoedema. Additionally, the pathophysiology of GO (and likely pretibial myxoedema) involves the synergism of insulin-like growth factor 1 receptor (IGF1R) with TSHR autoantibodies, causing retro-orbital tissue expansion and inflammation. Although the aetiology of GD remains unknown, evidence indicates a strong genetic component combined with random potential environmental insults in an immunologically susceptible individual. The treatment of GD has not changed substantially for many years and remains a choice between antithyroid drugs, radioiodine or surgery. However, antithyroid drug use can cause drug-induced embryopathy in pregnancy, radioiodine therapy can exacerbate GO and surgery can result in hypoparathyroidism or laryngeal nerve damage. Therefore, future studies should focus on improved drug management, and a number of important advances are on the horizon. Graves’ disease is an autoimmune disease caused by autoantibodies to the thyroid-stimulating hormone receptor, causing hyperthyroidism. In this Primer, Davies and colleagues discuss the epidemiology, pathophysiology and diagnosis of Graves’ disease and highlight the need for better therapeutics for its management.

Hypertension is a leading risk factor for morbidity and mortality worldwide. Despite current anti-hypertensive therapies, most individuals with hypertension fail to achieve adequate blood pressure control. Moreover, even with adequate control, a residual risk of cardiovascular events and associated organ damage remains. These findings suggest that current treatment modalities are not addressing a key element of the underlying pathology. Emerging evidence implicates immune cells as key mediators in the development and progression of hypertension. In this Review, we discuss our current understanding of the diverse roles of innate and adaptive immune cells in hypertension, highlighting key findings from human and rodent studies. We explore mechanisms by which these immune cells promote hypertensive pathophysiology, shedding light on their multifaceted involvement. In addition, we highlight advances in our understanding of autoimmunity, HIV and immune checkpoints that provide valuable insight into mechanisms of chronic and dysregulated inflammation in hypertension.This Review outlines the roles of innate and adaptive immune cells in hypertension. The authors discuss the mechanisms and important properties of immune cells that contribute to hypertension pathogenesis, such as memory and plasticity.

Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.

Key Points HIV infection leads to perturbations of all of the main cell types of the immune system, including B cells. Most B-cell perturbations are associated with indirect effects of ongoing HIV replication, although some perturbations arise regardless of the decrease in viraemia by effective antiretroviral therapy (ART). Many B-cell defects in HIV infection are associated with alterations in the B-cell subpopulations that circulate in the peripheral blood. Most B cells in healthy individuals comprise resting naive and memory B cells, whereas several minor subpopulations are over-represented in HIV-infected individuals, including immature transitional B cells, exhausted B cells, activated mature B cells and plasmablasts. In vitro and in vivo studies show that HIV can also interact directly with B cells, although the frequency of these interactions is unlikely to account for the extent of B-cell dysregulation that is observed in infected individuals. HIV virions complexed with complement and antibody can bind B cells through the complement receptor CD21, and HIV virions and proteins, including gp120 and Nef, can also interact directly or indirectly with B cells. Indirect effects of HIV viraemia on B cells include B-cell hyperactivity (as manifested by hypergammaglobulinaemia), increased B-cell polyclonal activation, increased B-cell turnover, increased expression of activation markers and of markers that are associated with activation-induced apoptosis, increased frequency of B-cell malignancies and increased differentiation of B cells to plasmablasts. HIV viraemia with CD4 + T-cell lymphopenia is associated with an increased frequency of immature transitional B cells. This increase is also associated with increased serum levels of interleukin-7. HIV viraemia leads to B-cell exhaustion, as manifested by increased expression of multiple inhibitory receptors, altered expression of homing receptors, decreased cell division and somatic hypermutation in vivo , decreased proliferative and effector properties in vitro and enrichment of HIV-specific responses in the exhausted B-cell compartment. Although most B-cell perturbations in HIV-infected individuals are attributed to viraemia and are reversible by ART, one important exception is the loss of memory B cells. All stages of HIV infection are associated with a decrease both in the frequency of resting memory B cells and of B-cell responses against T-cell-dependent and T-cell-independent antigens. Many B-cell perturbations observed in HIV infection also arise in various infectious and non-infectious disease settings that involve immune dysfunction. Several human diseases that affect B cells show dysregulation of immature transitional B cells, whereas others show dysregulation of memory B cells, with alterations that are similar to B-cell exhaustion and activation-induced terminal differentiation. This article looks at the dysregulation of specific B-cell subpopulations that is associated with chronic HIV infection, with a view to understanding the mechanisms of B-cell pathogenesis in HIV-associated disease and other diseases that are characterized by immune dysfunction. In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4 + T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction.

Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistentHIVin such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4+ T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4+ T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4+ T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around theGALTof HIV-infected individuals despite long-term viral suppression and suggest that theGALTmayplay a major role in the persistence of HIV in such individuals.

The rapid spread of the new Coronavirus Disease 2019 (COVID-19) has actually become the newest challenge for the healthcare system since, to date, there is not an effective treatment. Among all drugs tested, Hydroxychloroquine (HCQ) has attracted significant attention. This systematic review aims to analyze preclinical and clinical studies on HCQ potential use in viral infection and chronic diseases. A systematic search of Scopus and PubMed databases was performed to identify clinical and preclinical studies on this argument; 2463 papers were identified and 133 studies were included. Regarding HCQ activity against COVID-19, it was noticed that despite the first data were promising, the latest outcomes highlighted the ineffectiveness of HCQ in the treatment of viral infection. Several trials have seen that HCQ administration did not improve severe illness and did not prevent the infection outbreak after virus exposure. By contrast, HCQ arises as a first-line treatment in managing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome. It also improves glucose and lipid homeostasis and reveals significant antibacterial activity.