Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection

Hunt, Peter W.; Sinclair, Elizabeth; Rodrı́guez, Benigno; Shive, Carey L.; Clagett, Brian; Funderburg, Nicholas T.; Robinson, Janet; Huang, Yong; Epling, Lorrie; Martin, Jeffrey N.; Deeks, Steven G.; Meinert, Curtis L.; Natta, Mark L. Van; Jabs, Douglas A.; Lederman, Michael M.

doi:10.1093/infdis/jiu238

Cited by 447 publications

(512 citation statements)

References 49 publications

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“…Indices of inflammation and coagulation are heightened in ART-suppressed HIV-infected persons, particularly in patients with suboptimal CD4 + T-cell reconstitution [39,40], and these indices predict cardiovascular risk [41,42]. Circulating immune cells can interact with soluble coagulation elements through expression of the thrombin receptor PAR-1.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

et al. 2016

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Increases in inflammation, coagulation, and CD8 + T-cell numbers are associated with an elevated cardiovascular disease (CVD) risk in human immunodeficiency virus (HIV)-infected antiretroviral therapy (ART) recipients. Circulating memory CD8 + T cells that express the vascular endothelium-homing receptor CX3CR1 (fractalkine receptor) are enriched in HIV-infected ART recipients. Thrombin-activated receptor (PAR-1) expression is increased in HIV-infected ART recipients and is particularly elevated on CX3CR1 + CD8 + T cells, suggesting that these cells could interact with coagulation elements. Indeed, thrombin directly enhanced T-cell receptor-mediated interferon γ production by purified CD8 + T cells but was attenuated by thrombin-induced release of transforming growth factor β by platelets. We have therefore identified a population of circulating memory CD8 + T cells in HIV infection that may home to endothelium, can be activated by clot-forming elements, and are susceptible to platelet-mediated regulation. Complex interactions between inflammatory elements and coagulation at endothelial surfaces may play an important role in CVD risk in HIV-infected ART recipients.

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Section: Discussionmentioning

confidence: 99%

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

et al. 2016

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“…15,17,33 Among these studies, sCD14 was reported to be associated with coronary calcification, an indicator of atherosclerosis in HIV-1-infected patients on cART. 15 It was also reported that in HIV-1-infected patients, sCD14 together with gut epithelial barrier dysfunction was predictive of increased mortality.…”

Section: Discussionmentioning

confidence: 99%

“…7,9,21 However, others have not found any association between CMV IgG and non-AIDS-defining conditions in cART-suppressed patients. 16,33 Therefore the pathogenesis of CMV coinfection in cART-treated HIV-infected patients remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…7,16,21,33,34 The study was designed to quantitate and compare levels of CMV IgG with levels of markers of inflammation and immune activation across three groups of women: (1) HIV seronegative, (2) HIV seropositive/viremic, and (3) HIV seropositive/aviremic. We sought to test whether CMV IgG levels were associated with the levels of HIV viremia and the levels of these markers and whether the observed associations remained after adjustment for known sociodemographic and clinical confounders.…”

Section: Introductionmentioning

confidence: 99%

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The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

Lurain

Hanson

Hotton

et al. 2016

AIDS Research and Human Retroviruses

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Three groups of cytomegalovirus (CMV)-seropositive women (total n = 164) were selected from the Chicago Women's Interagency HIV-1 Study to investigate the association between CMV coinfection and immune activation: (1) HIV-1 viremic, (2) HIV-1 aviremic, and (3) HIV-1 uninfected. Quantitative measures of CMV serum IgG, CMV DNA, and serum biomarkers interleukin (IL)-6, soluble CD163 (sCD163), soluble CD14 (sCD14), and interferon gamma-induced protein (IP10) were obtained. Levels of CMV IgG and the serum biomarkers were significantly higher in the HIV-1 viremic group compared to the aviremic and uninfected groups ( p < 0.001). No significant associations with CMV IgG levels were found for HIV-uninfected women. When each of the HIVinfected groups was analyzed, sCD14 levels in the viremic women were significantly associated with CMV IgG levels with p < 0.02 when adjusted for age, CD4 count, and HIV viral load. There was also a modest association ( p = 0.036) with IL-6 from plasma and cervical vaginal lavage specimens both unadjusted and adjusted for CD4 count and HIV viral load. The association of CMV IgG level with sCD14 implicates the monocyte as a potential site for interaction of the two viruses, which eventually may lead to non-AIDS-defining pathological conditions.

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“…Furthermore, no consistent effect on soluble markers of inflammation was observed, and these markers have a stronger association with clinical outcomes in patients on ART than do cellular markers of immune activation. 11,29 Any effect on immune activation in the off-ART study was confounded by enhancement of viral replication by chloroquine, which itself may have driven greater immune activation as suggested by a significant correlation between changes in plasma viremia and CD8 T-cell activation. Assessment in the on-ART cohort removed HIV replication as a potentially confounding driver of activation, although it is possible that chloroquine could have induced low-level viral replication, only detectable by single copy assay, in this cohort.…”

Section: Figmentioning

confidence: 99%

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

Jacobson

Bosinger

Kang

et al. 2016

AIDS Research and Human Retroviruses

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Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log 10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquinetreated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.

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Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection

Abstract: Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.

Cited by 447 publications

References 49 publications

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

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Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection

Abstract: Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.

Cited by 447 publications

References 49 publications

Inflammatory Function of CX3CR1+CD8+T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

Inflammatory Function of CX3CR1+CD8+T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

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Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions