HIV-Infected Individuals on ART With Impaired Immune Recovery Have Altered Plasma Metabolite Profiles

Abstract

Background: Multiple host factors may influence immune reconstitution in HIV-infected people after the initiation of suppressive antiretroviral therapy (ART). Aberrant metabolic pathways have been reported in people with HIV (PWH) on ART. We hypothesized that alterations in plasma metabolites were associated with immune recovery following ART.

Methods: In this cross-sectional study, the plasma metabolomic profiles of PWH on ART were evaluated. PWH of slow and fast immune recovery were classified by increase in CD4 T cells following 2 years of ART. Targeted plasma metabolite profiling by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry to determine metabolite signatures for HIV recovery identified >200 metabolites.

Results: Notably, indole-3-propionic acid was downregulated during HIV, possibly reflecting impaired gastrointestinal epithelium homeostasis. The most important metabolite discriminating between the PWH with fast and slow immune recovery was cysteine. Upregulated cysteine and cysteine pathways may contribute to redox-balance maintenance and T-cell function in PWH with fast immune recovery. Additionally, serine and glycine metabolism and bile acid biosynthesis were the most perturbed metabolic pathways in PWH.

Conclusions: These results provide a starting point for developing biomarker candidates for immune recovery in PWH on ART and provide insight into the interplay of metabolism and immune response in HIV infection.

Keywords: HIV; antiretroviral therapy; immune recovery; metabolomics.

Figure 1.

Partial least-squares discriminant analysis (PLS-DA) of gas chromatography–mass spectrometry (GC-MS) plasma metabolites. GC-MS data, comparing the plasma metabolites of HIV-positive individuals with fast immune recovery (fast, n = 70) and HIV-negative controls (control, n = 65) (A) and HIV-positive individuals with slow immune recovery (slow, n = 50) and HIV-negative controls (B).

Figure 2.

Partial least-squares discriminant analysis (PLS-DA) of liquid chromatography–mass spectrometry (LC-MS) plasma metabolites. LC-MS-positive mode data, comparing the plasma metabolites of HIV-positive individuals with fast immune recovery (fast, n = 71) and HIV-negative controls (control, n = 70) (A) and HIV-positive individuals with slow immune recovery (slow; n = 50) and HIV-negative controls (B). C and D, LC-MS-negative mode data.

Figure 3.

Plasma levels of single metabolites and CD4 T-cell numbers. Univariate statistical analysis of plasma indole-3-propionic acid (IPA), tryptophan, kynurenine, and kynurenate (A). Cysteine levels are presented as arbitrary units (AU) (B). B, Spearman correlation of cysteine plasma intensity and CD4 number in HIV-positive individuals. Medians and 5th–95th percentiles are shown. ^***P < .001, Kruskal-Wallis test with Dunn’s post-test. Fast n = 70, slow n = 50, and controls n = 65.

Figure 4.

Metabolite set enrichment analysis gas chromatography–mass spectrometry. Summary plot of over-representation analysis of plasma metabolites in HIV-positive individuals with fast immune recovery (A) and slow immune recovery (B) compared with HIV-negative controls.

Figure 5.

Metabolite set enrichment analysis liquid chromatography–mass spectrometry. Summary plot of over-representation analysis of plasma metabolites in HIV-positive individuals with fast immune recovery (A) and slow immune recovery (B) compared with HIV-negative controls.