Microbial Translocation in HIV Infection Is Associated With Dyslipidemia, Insulin Resistance, and Risk of Myocardial Infarction

Objective:Microbial translocation has been suggested to be a driver of immune activation and inflammation. It is hypothesized that microbial translocation may be related to dyslipidemia, insulin resistance, and the risk of coronary heart disease in HIV-infected individuals. Design:Cross-sectional study of 60 HIV-infected patients on combination antiretroviral therapy with viral suppression >2 years and 31 healthy age-matched controls. Methods:Lipopolysaccharide (LPS) was analyzed by limulus amebocyte lysate colorimetric assay. Lipids, including cholesterol, low-density lipoprotein (LDL), and triglycerides, were measured. Glucose metabolism was determined using an oral glucose tolerance test. Body composition was determined using whole-body dual-energy x-ray absorptiometry scans and magnetic resonance imaging. The Framingham risk score was used to assess risk of cardiovascular disease and myocardial infarction. Results:HIV-infected patients had higher level of LPS compared with controls (64 pg/mL vs. 50 pg/mL, P = 0.002). Likewise, HIV-infected patients had higher triglycerides, LDL, and fasting insulin as well as evidence of lower insulin sensitivity compared with controls. Among HIV-infected patients, high LPS was associated with a higher level of triglycerides and LDL and with lower insulin sensitivity. Importantly, among HIV-infected patients, high LPS was associated with a higher Framingham risk score. Conclusions:HIV-infected patients with suppressed viral replication had increased level of microbial translocation as measured by LPS. LPS was associated with cardiometabolic risk factors and increased Framingham risk score. Hence, the gastrointestinal mucosal barrier may be a potential therapeutic target to prevent dyslipidemia and future cardiovascular complications in HIV infection.

[1]  H. Ullum,et al.  Persisting Inflammation and Chronic Immune Activation but Intact Cognitive Function in HIV-Infected Patients After Long-Term Treatment With Combination Antiretroviral Therapy , 2013, Journal of acquired immune deficiency syndromes.

[2]  T. Kanda,et al.  Circulating levels of HMGB1 are correlated strongly with MD2 in HIV-infection: Possible implication for TLR4-signalling and chronic immune activation , 2013, Innate immunity.

[3]  U. Bredeek,et al.  SWIFT: Prospective 48-Week Study to Evaluate Efficacy and Safety of Switching to Emtricitabine/Tenofovir From Lamivudine/Abacavir in Virologically Suppressed HIV-1 Infected Patients on a Boosted Protease Inhibitor Containing Antiretroviral Regimen , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  B. Pedersen,et al.  Cognitive Functions in Middle Aged Individuals Are Related to Metabolic Disturbances and Aerobic Capacity: A Cross-Sectional Study , 2012, PloS one.

[5]  D. Douek,et al.  Microbial translocation in HIV infection: causes, consequences and treatment opportunities , 2012, Nature Reviews Microbiology.

[6]  R. Maserati,et al.  Switching to Tenofovir/Emtricitabine from Abacavir/ Lamivudine in HIV-Infected Adults with Raised Cholesterol: Effect on Lipid Profiles , 2012, Antiviral therapy.

[7]  A. Sönnerborg,et al.  Impact of HMGB1/TLR Ligand Complexes on HIV-1 Replication: Possible Role for Flagellin during HIV-1 Infection , 2012, International journal of microbiology.

[8]  E. Martinez,et al.  Fat redistribution syndromes associated with HIV-1 infection and combination antiretroviral therapy. , 2012, AIDS reviews.

[9]  Jeffrey N. Martin,et al.  Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy , 2011, AIDS.

[10]  S. Lewin,et al.  Antibody and B-cell responses may control circulating lipopolysaccharide in patients with HIV infection , 2011, AIDS.

[11]  A. Rissanen,et al.  Bacterial Endotoxin Activity in Human Serum Is Associated With Dyslipidemia, Insulin Resistance, Obesity, and Chronic Inflammation , 2011, Diabetes Care.

[12]  M. Fresno,et al.  Toll-like receptors, inflammation, metabolism and obesity , 2011, Archives of physiology and biochemistry.

[13]  A. d’Arminio Monforte,et al.  Evidence for Polymicrobic Flora Translocating in Peripheral Blood of HIV-Infected Patients with Poor Immune Response to Antiretroviral Therapy , 2011, PloS one.

[14]  R. Kaul,et al.  Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy , 2011, AIDS.

[15]  Handan Wand,et al.  Plasma levels of soluble CD14 independently predict mortality in HIV infection. , 2011, The Journal of infectious diseases.

[16]  V. Salomaa,et al.  Endotoxemia Is Associated With an Increased Risk of Incident Diabetes , 2011, Diabetes Care.

[17]  S. Deeks,et al.  HIV infection, inflammation, immunosenescence, and aging. , 2011, Annual review of medicine.

[18]  L. Putignani,et al.  Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. , 2010, Endocrine reviews.

[19]  J. Brüning,et al.  CNS leptin and insulin action in the control of energy homeostasis , 2010, Annals of the New York Academy of Sciences.

[20]  A. Mocroft,et al.  Serious Fatal and Nonfatal Non-AIDS-Defining Illnesses in Europe , 2010, Journal of acquired immune deficiency syndromes.

[21]  B. Rice,et al.  HIV transmission and high rates of late diagnoses among adults aged 50 years and over , 2010, AIDS.

[22]  S. Pittaluga,et al.  Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections , 2010, PLoS pathogens.

[23]  A. Sönnerborg,et al.  Elevated plasma levels of lipopolysaccharide and high mobility group box-1 protein are associated with high viral load in HIV-1 infection: reduction by 2-year antiretroviral therapy , 2010, AIDS.

[24]  O. Kirk,et al.  Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D study , 2010, AIDS.

[25]  A. Mocroft,et al.  Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV , 2010, AIDS.

[26]  O. Kirk,et al.  Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. , 2010, The Journal of infectious diseases.

[27]  M. Carrascal,et al.  Lipoprotein lipase is nitrated in vivo after lipopolysaccharide challenge. , 2009, Free radical biology & medicine.

[28]  M. Lorenzo,et al.  Molecular mechanisms involved in obesity-associated insulin resistance: Therapeutical approach , 2009, Archives of physiology and biochemistry.

[29]  R. Ebrahimi,et al.  A Randomized Comparative Trial of Continued Zidovudine/Lamivudine or Replacement With Tenofovir Disoproxil Fumarate/Emtricitabine in Efavirenz-Treated HIV-1-Infected Individuals , 2009, Journal of acquired immune deficiency syndromes.

[30]  M. Lederman,et al.  Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. , 2009, The Journal of infectious diseases.

[31]  Jeffrey N. Martin,et al.  Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  W. D. de Villiers,et al.  Chylomicrons promote intestinal absorption of lipopolysaccharides Published, JLR Papers in Press, September 24, 2008. , 2009, Journal of Lipid Research.

[33]  D. Douek,et al.  Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. , 2008, Blood.

[34]  J. Lundgren.  Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients , 2008, AIDS.

[35]  C. Latkin,et al.  Correlates of Lending Needles/Syringes Among HIV-Seropositive Injection Drug Users , 2007, Journal of acquired immune deficiency syndromes.

[36]  D. Webb,et al.  A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. , 2007, The American journal of clinical nutrition.

[37]  C. Katlama,et al.  HIV-Infected Adults With a CD4 Cell Count Greater Than 500 Cells/mm3 on Long-Term Combination Antiretroviral Therapy Reach Same Mortality Rates as the General Population , 2007, Journal of acquired immune deficiency syndromes.

[38]  Hang Lee,et al.  Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. , 2007, The Journal of clinical endocrinology and metabolism.

[39]  J. Ferrières,et al.  Metabolic Endotoxemia Initiates Obesity and Insulin Resistance , 2007, Diabetes.

[40]  H. Sørensen,et al.  Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[41]  O. Kirk,et al.  Class of antiretroviral drugs and the risk of myocardial infarction. , 2007, The New England journal of medicine.

[42]  Gitte Pedersen,et al.  Survival of Persons with and without HIV Infection in Denmark, 19952005 , 2007, Annals of Internal Medicine.

[43]  J. Brenchley,et al.  Microbial translocation is a cause of systemic immune activation in chronic HIV infection , 2006, Retrovirology.

[44]  A. Milinkovic.  HIV-associated lipodystrophy syndrome. , 2006, Collegium antropologicum.

[45]  J. Cohn,et al.  Arterial elasticity as part of a comprehensive assessment of cardiovascular risk and drug treatment. , 2005, Hypertension.

[46]  Stephen R Cole,et al.  Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. , 2005, Archives of internal medicine.

[47]  D. Price,et al.  CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract , 2004, The Journal of experimental medicine.

[48]  Christine Hogan,et al.  Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract , 2004, The Journal of experimental medicine.

[49]  J. Flamm,et al.  Severe CD4+ T-Cell Depletion in Gut Lymphoid Tissue during Primary Human Immunodeficiency Virus Type 1 Infection and Substantial Delay in Restoration following Highly Active Antiretroviral Therapy , 2003, Journal of Virology.

[50]  P. Limone,et al.  Insulin resistance in HIV-infected patients: relationship with pro-inflammatory cytokines released by peripheral leukocytes. , 2003, The Journal of infection.

[51]  S. Cole,et al.  Impact of HIV infection and HAART on serum lipids in men. , 2003, JAMA.

[52]  S. Goldblum,et al.  Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[53]  Jeffrey N. Martin,et al.  T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. , 2003, The Journal of infectious diseases.

[54]  G. Chrousos,et al.  AIDS-Related Lipodystrophy/Insulin Resistance Syndrome , 2003, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[55]  O. Kirk,et al.  Modelling the 3‐year risk of myocardial infarction among participants in the Data Collection on Adverse Events of Anti‐HIV Drugs (DAD) study , 2003, HIV medicine.

[56]  S. Kiechl,et al.  Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. , 1999, Journal of the American College of Cardiology.

[57]  I. Fong,et al.  In vivo cytokine and neuroendocrine responses to endotoxin in human immunodeficiency virus-infected subjects. , 1999, The Journal of infectious diseases.

[58]  M. Matsuda,et al.  Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. , 1999, Diabetes care.

[59]  J V Giorgi,et al.  Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. , 1999, The Journal of infectious diseases.

[60]  J. Gold,et al.  Validation of a combined comorbidity index. , 1994, Journal of clinical epidemiology.

[61]  A. Walsh,et al.  In vivo protection against endotoxin by plasma high density lipoprotein. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[62]  F. Månsson,et al.  Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections. , 2010, The Journal of infectious diseases.

[63]  C. Apovian.  A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation , 2008 .

[64]  D. Douek,et al.  HIV infection and the gastrointestinal immune system , 2008, Mucosal Immunology.

[65]  K. Anderson,et al.  Cardiovascular disease risk profiles. , 1991, American heart journal.

[66]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.