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      Incidence and Risk Factors for Severe Bacterial Infections in People Living with HIV. ANRS CO3 Aquitaine Cohort, 2000–2012

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          Abstract

          Severe non-AIDS bacterial infections (SBI) are the leading cause of hospital admissions among people living with HIV (PLHIV) in industrialized countries. We aimed to estimate the incidence of SBI and their risk factors in a large prospective cohort of PLHIV patients over a 13-year period in France. Patients followed up in the ANRS CO3 Aquitaine cohort between 2000 and 2012 were eligible; SBI was defined as a clinical diagnosis associated with hospitalization of ≥48 hours or death. Survival analysis was conducted to identify risk factors for SBI.Total follow-up duration was 39,256 person-years [PY] (31,370 PY on antiretroviral treatment [ART]). The incidence of SBI decreased from 26.7/1000 PY [95% CI: 22.9–30.5] over the period 2000–2002 to 11.9/1000 PY [10.1–13.8] in 2009–2012 (p <0.0001). Factors independently associated to increased risk of SBI were: plasma HIVRNA>50 copies/mL (Hazard Ratio [HR] = 5.1, 95% Confidence Interval: 4.2–6.2), CD4 count <500 cells/mm 3 and CD4/CD8 ratio <0.8 (with a dose-response relationship for both markers), history of cancer (HR = 1.4 [1.0–1.9]), AIDS stage (HR = 1.7 [1.3–2.1]) and HCV coinfection (HR = 1.4, [1.1–1.6]). HIV-positive patients with diabetes were more prone to SBI (HR = 1.6 [0.9–2.6]). Incidence of SBI decreased over a 13-year period due to the improvement in the virological and immune status of PLHIV on ART. Risk factors for SBI include low CD4 count and detectable HIV RNA, but also CD4/CD8 ratio, HCV coinfection, history of cancer and diabetes, comorbid conditions that have been frequent among PLHIV in recent years.

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          Microbial translocation is a cause of systemic immune activation in chronic HIV infection

          Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here, we show that circulating microbial products, likely derived from the gastrointestinal tract, are a primary cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, an indicator of microbial translocation, is significantly increased in chronically HIV-infected individuals and SIV-infected rhesus macaques. We show that monocytes are chronically stimulated in vivo by increased lipopolysaccharide, which also correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy appears to reduce microbial translocation. Furthermore, in non-pathogenic SIV infection of sooty mangabeys, microbial translocation does not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide novel directions for therapeutic interventions that modify the consequences of acute HIV infection.
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            Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections.

            Diabetes has been recognized as an important risk factor for a variety of intracellular bacterial infections, but research into the dysregulated immune mechanisms contributing to the impaired host-pathogen interactions is in its infancy. Diabetes is characterized by a chronic state of low-grade inflammation due to activation of pro-inflammatory mediators and increased formation of advanced glycation end products. Increased oxidative stress also exacerbates the chronic inflammatory processes observed in diabetes. The reduced phagocytic and antibacterial activity of neutrophils and macrophages provides an intracellular niche for the pathogen to replicate. Phagocytic and antibacterial dysfunction may be mediated directly through altered glucose metabolism and oxidative stress. Furthermore, impaired activation of natural killer cells contributes to decreased levels of interferon-γ, required for promoting macrophage antibacterial mechanisms. Together with impaired dendritic cell function, this impedes timely activation of adaptive immune responses. Increased intracellular oxidation of antigen-presenting cells in individuals with diabetes alters the cytokine profile generated and the subsequent balance of T-cell immunity. The establishment of acute intracellular bacterial infections in the diabetic host is associated with impaired T-cell-mediated immune responses. Concomitant to the greater intracellular bacterial burden and potential cumulative effect of chronic inflammatory processes, late hyper-inflammatory cytokine responses are often observed in individuals with diabetes, contributing to systemic pathology. The convergence of intracellular bacterial infections and diabetes poses new challenges for immunologists, providing the impetus for multidisciplinary research. © 2014 John Wiley & Sons Ltd.
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              HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 April 2016
                2016
                : 11
                : 4
                : e0152970
                Affiliations
                [1 ]Centre Hospitalier Universitaire (CHU) Bordeaux, Coordination régionale de la lutte contre l’infection à VIH (COREVIH), Bordeaux, France
                [2 ]CHU Bordeaux, Services de médecine interne et maladies infectieuses, Bordeaux, France
                [3 ]Université de Bordeaux, ISPED, Centre INSERM U897- Epidémiologie-Biostatistique Rue Léo Saignat, Bordeaux, France
                [4 ]INSERM U897, Centre Inserm Epidémiologie et Biostatistique, Université de Bordeaux, Rue Léo Saignat, Bordeaux, France
                [5 ]CHU Bordeaux, Service de Médecine Interne et Maladies Infectieuses, Pessac, France
                [6 ]CHU Bordeaux, Fédération de maladies infectieuses et tropicales, Bordeaux, France
                [7 ]CH de Dax, Service de Maladies Infectieuses, Dax, France
                FIOCRUZ, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AC MAV EL PD CC YG FD FB. Performed the experiments: AC MAV EL PD CC YG. Analyzed the data: FLM MB FD FB. Contributed reagents/materials/analysis tools: FLM MB FD FB. Wrote the paper: AC FLM MAV EL PD CC YG FD MB FB.

                ¶ Membership of the ANRS CO3 Aquitaine Cohort Study Group is listed in the Acknowledgments.

                Article
                PONE-D-15-45564
                10.1371/journal.pone.0152970
                4822811
                27050752
                4bdf86da-96a3-4881-84ff-be85eb48558a
                © 2016 Collin et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 October 2015
                : 22 March 2016
                Page count
                Figures: 2, Tables: 2, Pages: 12
                Funding
                This work is supported by a grant of France Recherche Nord&Sud Sida-HIV Hépatites (ANRS) within the Coordinated Action no. 7 (AC7). Other sources of support include the Bordeaux University Hospital through the COREVIH Aquitaine, Inserm (U897) and the Bordeaux School of Public Health (ISPED). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Infectious Diseases
                Bacterial Diseases
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Immunodeficiency Viruses
                HIV
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Viral Pathogens
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                HIV
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                Public and Occupational Health
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