Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV

Giron, Leila B.; Palmer, Clovis S.; Liu, Qin; Yin, Xiangfan; Papasavvas, Emmanouil; Damra, Mohammad; Goldman, Aaron R.; Tang, Hsin‐Yao; Johnston, Rowena; Mounzer, Karam Mounzer; Kostman, Jay R.; Tebas, Pablo; Landay, Alan; Montaner, Luis J.; Jacobson, Jeffrey M.; Li, Jonathan; Abdel‐Mohsen, Mohamed

doi:10.21203/rs.3.rs-102034/v1

Cited by 8 publications

(14 citation statements)

References 83 publications

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“…Untargeted measurement of Plasma metabolites. Metabolomics analysis was performed as described previously (145,146). Briefly, polar metabolites were extracted with 80% methanol.…”

Section: Measurement Of Plasma Markers Of Inflammationmentioning

confidence: 99%

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Giron¹,

Peluso²,

Ding³

et al. 2022

JCI Insight

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Long COVID, a type of Post-Acute Sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 could be exacerbated by microbial translocation (from gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation -measured as β-glucan, a fungal cell wall polysaccharide -in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls.The higher β-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling.Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from negative controls. This higher NF-κB signaling was abrogated by Piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

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“…Untargeted measurement of Plasma metabolites. Metabolomics analysis was performed as described previously (145,146). Briefly, polar metabolites were extracted with 80% methanol.…”

Section: Measurement Of Plasma Markers Of Inflammationmentioning

confidence: 99%

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Giron¹,

Peluso²,

Ding³

et al. 2022

JCI Insight

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“…This correlation suggests that many US transcripts originate from defective HIV genomes, which in theory might raise concerns as to the significance of US RNA as a predictive marker for viral rebound. However, a number of studies have demonstrated this marker to be a powerful predictor of viral rebound, suggesting its value as surrogate for the active replication-competent HIV reservoir [49 ▪▪ ,53–54,55 ▪▪ ,60 ▪ ]. We demonstrated that US RNA was predictive not only of the time to viral rebound to both >50 and >400 copies/ml but also of the magnitude of the viral rebound, independently of pre-ART virological biomarkers [55 ▪▪ ].…”

Section: Viral Biomarkers Of Virological Remission and Posttreatment ...mentioning

confidence: 66%

“…This concept is based on the assumption that such a composite molecular profile is expected to outperform each of the individual component biomarkers by the predictive power for viral rebound. Interestingly, a similar concept was recently followed by Giron et al , who used a machine-learning algorithm to identify a set of plasma biomarkers that predicts the viral rebound and distinguishes PTCs from noncontrollers better than any of the single component biomarkers [49 ▪▪ ].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, a clear characteristic of PTC is a low total HIV DNA level, but this parameter has failed thus far as a biomarker to prospectively identify PTCs [17,41,46]. Interestingly, despite the fact that total HIV DNA largely overestimates the size of the genetically intact reservoir [47], it repeatedly outperformed the amount of intact provirus as a predictor of virological remission [48,49 ▪▪ ] and correlated with time to viral rebound in several studies [49 ▪▪ ,50–52], although other studies reported no association of HIV DNA and virological remission [53,54]. However, the devil might be in the details as these discrepancies could also be due to differences in the study populations.…”

Section: Viral Biomarkers Of Virological Remission and Posttreatment ...mentioning

confidence: 99%

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Towards a molecular profile of antiretroviral therapy-free HIV remission

Adams¹,

Berkhout²,

Pasternak³

2022

Current Opinion in HIV and AIDS

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Purpose of reviewTo summarize the current status and highlight recent findings on predictive biomarkers for posttreatment HIV control (PTC) and virological remission. While historically, many studies focused on virological markers, there is an increasing tendency to enter immune and metabolic factors into the equation. Recent findingsOn the virological side, several groups reported that cell-associated HIV RNA could predict time to viral rebound. Recent data hints at the possible importance of the genic location and chromatin context of the integrated provirus, although these factors still need to be assessed in relation to PTC and virological remission. Evidence from immunological studies highlighted innate and humoral immunity as important factors for prolonged HIV remission. Interestingly, novel metabolic markers have emerged, which offer additional angles to our understanding of latency and viral rebound. SummaryFacilitating PTC and virological remission remain top priorities for the HIV cure research. We advocate for clear and precise definitions for both phenomena in order to avoid misconceptions and to strengthen the conclusions that can be drawn. As no one-size-fits-all marker has emerged yet, more biomarkers are on the horizon, and viral rebound is a complex and heterogeneous process, it is likely that a combination of various biomarkers in cohesion will be necessary for a more accurate prediction of antiretroviral therapyfree HIV remission.

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“…Untargeted measurement of Plasma metabolites. Metabolomics analysis was performed as described previously (133,134). Briefly, polar metabolites were extracted with 80% methanol.…”

Section: Measurement Of Plasma Markers Of Inflammationmentioning

confidence: 99%

Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation

Giron

Peluso

Ding

et al. 2022

Preprint

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Long COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the pathophysiological mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 (COVID-19) could be exacerbated by microbial translocation (from the gut and/or lung) to the blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We found higher levels of fungal translocation - measured as beta-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher beta-glucan correlated with higher levels of markers of inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, beta-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-kB signaling. Using an in vitro Dectin-1/NF-kB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-kB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-kB signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

show abstract

Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV

Cited by 8 publications

References 83 publications

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Towards a molecular profile of antiretroviral therapy-free HIV remission

Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation

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