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

Pedersen, Kim Steenstrup; Pedersen, Maria; Trøseid, Marius; Gaardbo, Julie C.; Lund, Thomas Kromann; Thomsen, Carsten; Gerstoft, Jan; Kvale, Dag; Nielsen, Susanne Dam

doi:10.1097/qai.0b013e31829f919d

Cited by 80 publications

(61 citation statements)

References 62 publications

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“…In patients receiving ART, positive associations have recently been reported between plasma LPS and triglycerides, total cholesterol, and LDL cholesterol, respectively. 91 These findings are well in line with recent reports of strong correlations between LPS and both elevated fasting triglycerides and low HDL cholesterol, 92 as well as low levels of large particle HDL cholesterol. 93 Several mechanisms could explain these associations.…”

Section: Dyslipidemiasupporting

confidence: 91%

“…97 Insulin resistance and metabolic syndrome Interestingly, increased levels of plasma LPS correlate with lower insulin sensitivity in patients on ART. 91 Furthermore, in a cohort of ART-naive patients plasma LPS and triglycerides were independently associated and both markers correlated with the development of several factors associated with the metabolic syndrome, including high blood pressure, high body mass index, high levels of glucose and uric acid, as well as low levels of HDL cholesterol. 98 However, data on the potential impact of microbial translocation on diabetes mellitus are so far lacking in HIV-infected populations.…”

Section: Dyslipidemiamentioning

confidence: 99%

“…Indeed, HIV-infected patients within the highest LPS level strata had a significantly higher 10-year predicted risk of myocardial infarction and CVD 91 .…”

Section: Risk Of Cardiovascular Eventsmentioning

confidence: 99%

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Microbial Translocation and Cardiometabolic Risk Factors in HIV Infection

Trøseid

Manner

Pedersen

et al. 2014

AIDS Research and Human Retroviruses

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The widespread access to antiretroviral treatment during the past decades has transformed HIV infection from a lethal disease to a chronic condition, in which the relative burden of non-AIDS-related chronic disorders such as cardiovascular disease, malignancy, renal, liver, and bone disease has increased. The adjusted relative risk for myocardial infarction is reported to be around 2-fold compared to that of the general population, which over time is likely to translate into increased absolute risk in an aging population. Thus, delineating potentially HIV-specific pathogenetic mechanisms is crucial in order to tailor novel strategies for prophylaxis and treatment. This review will focus on advances in the field that possibly link HIV-induced alterations of the gut mucosa and consequent microbial translocation to cardiometabolic risk factors in HIV infection. Recent work suggests that markers of microbial translocation are closely associated with several cardiovascular risk factors such as dyslipidemia, insulin resistance, hypertension, coagulation abnormalities, endothelial dysfunction, and carotid atherosclerosis. Future studies should investigate whether associations between microbial translocation and cardiovascular risk factors will translate into increased risk of acute events, and whether strategies to target gut microbiota and microbial translocation might reduce such a risk.

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Section: Dyslipidemiasupporting

confidence: 91%

Section: Dyslipidemiamentioning

confidence: 99%

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Microbial Translocation and Cardiometabolic Risk Factors in HIV Infection

Trøseid

Manner

Pedersen

et al. 2014

AIDS Research and Human Retroviruses

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“…This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptophan into kynurenine (Kyn), which is mediated by the indoleamine 2,3-dioxygenase 1 (IDO-1) expressed in dendritic cells (DCs) and monocytes, is increased in HIV-1-infected subjects (22,(28)(29)(30).…”

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

“…As early HIV-1 infection is characterized by persistent inflammation and enhanced tryptophan catabolism (22,(24)(25)(26)(27)42), we first evaluated the levels of several proinflammatory molecules and Kyn in plasma from the PHI, CHI, and HIV free subjects. Consistent with earlier reports (22,25,43), we found higher levels of IL-6, sCD14, IP-10, and Kyn in PHI and CHI subjects than HIV free donors (Fig.…”

Section: Loss Of Memory Cd4 T Cells During Hiv-1 Infection Involves Dmentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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MRI Assessment of Treatment Response in HIV‐associated NAFLD: A Randomized Trial of a Stearoyl‐Coenzyme‐A‐Desaturase‐1 Inhibitor (ARRIVE Trial)

et al. 2019

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Aramchol, an oral stearoyl-coenzyme-A-desaturase-1 inhibitor, has been shown to reduce hepatic fat content in patients with primary nonalcoholic fatty liver disease (NAFLD); however, its effect in patients with human immunodeficiency virus (HIV)-associated NAFLD is unknown. The aramchol for HIV-associated NAFLD and lipodystrophy (ARRIVE) trial was a double-blind, randomized, investigator-initiated, placebo-controlled trial to test the efficacy of 12 weeks of treatment with aramchol versus placebo in HIV-associated NAFLD. Fifty patients with HIV-associated NAFLD, defined by magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) ≥5%, were randomized to receive either aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary endpoint was a change in hepatic fat as measured by MRI-PDFF in colocalized regions of interest. Secondary endpoints included changes in liver stiffness using magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE), and exploratory endpoints included changes in total-body fat and muscle depots on dual-energy X-ray absorptiometry (DXA), whole-body MRI, and cardiac MRI. The mean (± standard deviation) of age and body mass index were 48.2 ± 10.3 years and 30.7 ± 4.6 kg/m 2 , respectively. There was no difference in the reduction in mean MRI-PDFF between the aramchol group at -1.3% (baseline MRI-PDFF 15.6% versus end-of-treatment MRI-PDFF 14.4%, P = 0.24) and the placebo group at -1.4% (baseline MRI-PDFF 13.3% versus end-of-treatment MRI-PDFF 11.9%, P = 0.26). There was no difference in the relative decline in mean MRI-PDFF between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were no differences in MREderived and VCTE-derived liver stiffness and whole-body (fat and muscle) composition analysis by MRI or DXA. Compared to baseline, end-of-treatment aminotransferases were lower in the aramchol group but not in the placebo arm. There were no significant adverse events. Conclusion: Aramchol, over a 12-week period, did not reduce hepatic fat or change body fat and muscle composition by using MRI-based assessment in patients with HIV-associated NAFLD (clinicaltrials.gov ID:NCT02684591). (Hepatology 2019;70:1531-1545).

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

Cited by 80 publications

References 62 publications

Microbial Translocation and Cardiometabolic Risk Factors in HIV Infection

Microbial Translocation and Cardiometabolic Risk Factors in HIV Infection

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

MRI Assessment of Treatment Response in HIV‐associated NAFLD: A Randomized Trial of a Stearoyl‐Coenzyme‐A‐Desaturase‐1 Inhibitor (ARRIVE Trial)

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