Plasma sphingolipids in HIV-associated chronic obstructive pulmonary disease

Shane Hodgson, Timothy J Griffin, Cavan Reilly, Stephen Harvey, Bruce A Witthuhn, Brian J Sandri, Ken M Kunisaki, Chris H Wendt, Shane Hodgson, Timothy J Griffin, Cavan Reilly, Stephen Harvey, Bruce A Witthuhn, Brian J Sandri, Ken M Kunisaki, Chris H Wendt

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity in persons living with HIV (PLWH) and HIV appears to uniquely cause COPD, independent of smoking. The mechanisms by which HIV leads to COPD are not clear. The objective of this study was to identify metabolomic biomarkers and potential mechanistic pathways of HIV-associated COPD (HIV-COPD).

Methods: We performed case-control metabolite profiling via mass spectrometry in plasma from 38 individuals with HIV-COPD (cases), comparing to matched controls with/without HIV and with/without COPD. Untargeted metabolites of interest were identified with liquid chromatography with mass spectrometry (LC-MS/mass spectrometry (MS)), and targeted metabolomics for tryptophan (Trp) and kynurenine (Kyn) were measured by selective reaction monitoring (SRM) with LC-MS/MS. We used mixed-effects models to compare metabolite concentrations in cases compared with controls while controlling for relevant biological variables.

Results: We identified 1689 analytes associated with HIV-COPD at a false discovery rate (FDR) of 10%. In PLWH, we identified 263 analytes (10% FDR) between those with and without COPD. LC MS/MS identified Trp and 17 lipids, including sphingolipids and diacylglycerol. After adjusting for relevant covariates, the Kyn/Trp ratio measured by SRM was significantly higher in PLWH (p=0.022), but was not associated with COPD status (p=0.95).

Conclusions: There is a unique metabolite profile in HIV-COPD that includes sphingolipids. Trp metabolism is increased in HIV, but does not appear to independently contribute to HIV-COPD.

Trial registration numbers: NCT01810289, NCT01797367, NCT00608764.

Keywords: COPD Pathology; COPD ÀÜ Mechanisms; Immunodeficiency.

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
The top 25 analytes by relevant q-value differentially expressed in HIV with COPD. The top number is m/z and the bottom number is RT. Y-axis is intensity. (A) HIV− COPD−, (B) HIV+ COPD−, (C) HIV− COPD+, (D) HIV+ COPD+. COPD, chronic obstructive pulmonary disease; m/z, mass/charge; RT, retention time.
Figure 2
Figure 2
Lipids differentially expressed in HIV. The top number is m/z and the bottom number is RT. Y-axis is intensity. (A) HIV− COPD−, (B) HIV+ COPD−, (C) HIV− COPD+, (D) HIV+ COPD+. COPD, chronic obstructive pulmonary disease; m/z, mass/charge; RT, retention time.
Figure 3
Figure 3
(A) Plasma tryptophan concentrations. (B) Plasma kynurenine concentrations. (C) IDO activity as reflected by kynurenine/tryptophan ratio. COPD, chronic obstructive pulmonary disease; IDO, indoleamine-2,3-dioxygenase.

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