Immunologic Pathways That Predict Mortality in HIV-Infected Ugandans Initiating Antiretroviral Therapy

Lee, Sulggi; Byakwaga, Helen; Boum, Yap; Burdo, Tricia H.; Williams, Kenneth C.; Lederman, Michael M.; Huang, Yong; Tracy, Russell P.; Cao, Huyen; Haberer, Jessica; Kembabazi, Annet; Bangsberg, David R.; Martin, Jeffrey N.; Hunt, Peter W.

doi:10.1093/infdis/jix113

Cited by 41 publications

(46 citation statements)

References 14 publications

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“…For example, among ART-suppressed HIV-infected individuals in North America, innate immune activation and inflammatory markers were much more strongly predictive of mortality than T cell activation (the opposite inference from the pre-ART era) [19, 20], presumably because most of the causes of death were non-infectious in etiology (e.g., cardiovascular, non-AIDS cancer, etc). Conversely, among ART-suppressed individuals in resource-limited settings, where infectious complications remain much more important causes of death [16, 17], T cell activation and pathways conferring adaptive immune defects are much stronger predictors of mortality [21–23]. Thus, it would not be surprising if the final common immunologic pathways driving disease vary by end-organ complication.…”

Section: Persistent Immune Activation During Artmentioning

confidence: 99%

“…After more than two decades of research, it remains unclear whether CD38 and HLA-DR expression on CD4+ and CD8+ T cells are in and of themselves causally associated with disease or instead markers of exhaustion and/or dysfunction [32] in response to HIV, co-infection, or homeostasis- or activation-induced proliferation [33]. These markers continue to predict disease during ART-mediated viral suppression, but not as strongly as in the pre-ART era (when AIDS complications dominated) [19, 20, 22], and primarily in resource-limited settings [23]. …”

Section: Specific Immunologic Pathways That Predict Disease In Hiv Inmentioning

confidence: 99%

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Role of immune activation in progression to AIDS

Utay

Hunt

2016

Current Opinion in HIV and AIDS

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Purpose of the review To review recent insights into the impact of HIV-associated immune activation on AIDS and non-AIDS morbidity and mortality. Recent findings Immune activation has long been recognized as an important consequence of untreated HIV infection and predictor of AIDS progression, which declines but fails to normalize during suppressive antiretroviral therapy (ART), and continues to predict disease in this setting. Thus, a major research agenda is to develop novel therapies to reduce persistent immune activation in treated HIV infection. Yet, the optimal targets for interventions remain unclear. Both the specific root causes of immune activation and the many interconnected pathways of immune activation that are most likely to drive disease risk in HIV-infected individuals remain incompletely characterized, but recent studies have shed new light on these topics. Summary In the context of this review, we will summarize recent evidence helping to elucidate the immunologic pathways that appear most strongly predictive of infectious and non-infectious morbidity. We will also highlight the likelihood that not all root drivers of immune activation - and the discrete immunologic pathways to which they give rise - are likely to produce the same disease manifestations and/or be equally attenuated by early ART initiation.

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Section: Persistent Immune Activation During Artmentioning

confidence: 99%

Section: Specific Immunologic Pathways That Predict Disease In Hiv Inmentioning

confidence: 99%

Role of immune activation in progression to AIDS

Utay

Hunt

2016

Current Opinion in HIV and AIDS

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“…Importantly, these hallmarks of infection result in immune dysfunction that can often persist despite the initiation of antiretroviral therapy (ART). Immune dysfunction, as measured by type I IFN activity for example, is predictive of non-AIDS related morbidity and mortality in ART-treated individuals [ 3 – 6 ] and residual immune activation may account for the overall shorter life expectancy of HIV-infected subjects, particularly in those with incomplete immunologic restoration after ART initiation [ 7 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function

et al. 2018

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Untreated Human Immunodeficiency Virus (HIV) infection is characterized by intestinal epithelial barrier dysfunction and chronic inflammation, related features that are attenuated to variable degrees by suppressive antiretroviral therapy (ART). Specific mediators of intestinal epithelial cell (IEC) dysfunction and restoration during HIV disease and treatment have yet to be identified. We studied IECs isolated from intestinal biopsies by RNAseq and found that mRNA levels for the ubiquitin-modifying enzyme, A20, are upregulated in ART-treated individuals and are positively correlated with markers of epithelial function (e.g., CTNNB, CLDN4, and TJP1). In a murine intestinal organoid model, A20 expression was suppressed by interferon-alpha (IFNα), which is highly expressed during HIV viremia and induces IFN-mediated signaling. Notably, A20 deletion rendered intestinal organoids more susceptible to cell death and inhibition of barrier-related genes mediated by interferon-gamma (IFNγ), a cytokine also present at elevated levels during untreated infection. Furthermore, A20 specifically restricted expression of IL-17A-induced inflammatory genes in organoids. Finally, ART-suppressed chronically infected individuals treated with pegylated IFNα2a for five weeks demonstrated reduced expression of A20 in peripheral blood mononuclear cells. Our results are thus consistent with a model in which enhanced type I interferons suppress A20 levels, leading to IFNγ-mediated dysfunction. As such, variation in A20 expression during the course of HIV infection could underlie both the development of epithelial dysfunction before the initiation of ART and the recovery of intestinal epithelial integrity thereafter.Trial registrationClinicalTrials.gov Clinical Trial NCT00594880

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“…(4) Other studies have also shown that elevated D-dimer levels in PLHIV both before and after ART initiation are correlated with greater risk of non-AIDS events and mortality in resource-rich (2,5) and resource limited settings among populations with advanced HIV disease. (3,6,7). PLHIV appear to be at higher risk for venous thrombotic events (8,9) likely due to activation of coagulation pathways resulting in a pro-coagulant states (10,11) which are associated with immunodeficiency and active viral replication.…”

Section: Introductionmentioning

confidence: 99%

Changes in D-Dimer after initiation of antiretroviral therapy in adults living with HIV in Kenya

Teasdale

Hernández

Zerbe

et al. 2020

Preprint

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Background Increased coagulation biomarkers are associated with poor outcomes among people living with HIV(PLHIV). There are few data available from African cohorts demonstrating the effect of antiretroviral therapy (ART) on coagulation biomarkers. Methods From March 2014 to October 2014, ART-naïve PLHIV initiating non-nucleoside reverse transcriptase inhibitor-based ART were recruited from seven clinics in western Kenya and followed for up to 12 months. Demographics, clinical history and blood specimens were collected. Logistic regression models adjusted for intrasite clustering examined associations between viral load and D-Dimer at baseline. Mixed linear effects models were used to estimate mean change from baseline to six months overall, and by baseline viral load, sex and TB status at enrollment. Mean change in D-dimer at six months is reported on the log10 scale and as percentage change from baseline. Results Among 611 PLHIV enrolled, 66% were female, median age was 34 years (interquartile range (IQR) 29–43 years), 31 (5%) participants had tuberculosis and median viral load was 113,500 copies/mL (IQR: 23,600 − 399,000). At baseline, 311 (50.9%) PLHIV had elevated D-dimer (> 500 ng/mL) and median D-dimer was 516.4 ng/mL (IQR: 302.7-926.6) (log baseline D-dimer: 2.7, IQR: 2.5-3.0). Higher baseline D-dimer was significantly associated with higher viral load (p < 0.0001), female sex (p = 0.02) and tuberculosis (p=-0.02). After six months on ART, 518 (84.8%) PLHIV had achieved viral load < 1,000 copies/mL and median D-dimer was 390.0 (IQR: 236.6-656.9) (log D-dimer: 2.6, IQR: 2.4–2.8). Mean change in log D-dimer from baseline to six months was − 0.12 (95%CI -0.15, − 0.09) (p < 0.0001) indicating at 31.3% decline (95%CI -40.0, -23.0) in D-dimer levels over the first six months on ART. D-dimer decline after ART initiation was significantly greater among PLHIV with tuberculosis at treatment initiation

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Immunologic Pathways That Predict Mortality in HIV-Infected Ugandans Initiating Antiretroviral Therapy

Cited by 41 publications

References 14 publications

Role of immune activation in progression to AIDS

Role of immune activation in progression to AIDS

A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function

Changes in D-Dimer after initiation of antiretroviral therapy in adults living with HIV in Kenya

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