Association Between Gut Microbiota and CD4 Recovery in HIV-1 Infected Patients

Abstract

Composition of the gut microbiota has been linked with human immunedeficiency virus (HIV)-infected patients on antiretroviral therapy (ART). Evidence suggests that ART-treated patients with poor CD4⁺ T-cell recovery have higher levels of microbial translocation and immune activation. However, the association of the gut microbiota and immune recovery remains unclear. We performed a cross-sectional study on 30 healthy controls (HC) and 61 HIV-infected individuals, including 15 immunological ART responders (IRs), 20 immunological ART non-responders (INRs) and 26 untreated individuals (VU). IR and INR groups were classified by CD4⁺ T-cell counts of ≥350 cells/mm³ and <350 cells/mm³ after 2 years of ART, respectively. Each subject's gut microbiota composition was analyzed by metagenomics sequencing. Levels of CD4⁺ T cells, CD8⁺HLA-DR⁺ T cells and CD8⁺CD38⁺ T cells were measured by flow cytometry. We identified more Prevotella and fewer Bacteroides in HIV-infected individuals than in HC. Patients in INR group were enriched with Faecalibacterium prausnitzii, unclassified Subdoligranulum sp. and Coprococcus comes when compared with those in IR group. F. prausnitzii and unclassified Subdoligranulum sp. were overrepresented in individuals in VU group with CD4⁺ T-cell counts <350 cells/mm³. Moreover, we found that the relative abundance of unclassified Subdoligranulum sp. and C. comes were positively correlated with CD8⁺HLA-DR⁺ T-cell count and CD8⁺HLA-DR⁺/CD8⁺ percentage. Our study has shown that gut microbiota changes were associated with CD4⁺ T-cell counts and immune activation in HIV-infected subjects. Interventions to reverse gut dysbiosis and inhibit immune activation could be a new strategy for improving immune reconstitution of HIV-1-infected individuals.

Keywords: CD4 recovery; HIV-infected individuals; butyrate-producing bacteria; gut microbiota; metagenomics sequencing.

FIGURE 1

(A) Principal coordinates analysis (PCoA) using Bray–Curtis dissimilarity distance. (B) Distribution of VU, IR, INR, and HC in enterotypes. The areas of the columns scale with sample size, that is, n = 26, 20, 15, and 30, respectively. (C) Relative abundances of Bacteroides and Prevotella in the two community types. (D) Relative abundance of species different between VU and healthy groups. Only the median relative abundances greater than 0.1% of total abundance are included (FDR < 0.1, Wilcoxon rank-sum test corrected by the Benjamini and Hochberg method).

FIGURE 2

(A) Differentially abundant species in the IR and INR groups. Only the median relative abundances greater than 0.1% of total abundance are included (FDR < 0.3, Wilcoxon rank-sum test corrected by the Benjamini and Hochberg method). (B) PCoA analysis based on the relative abundance of species different between IR and INR groups. (C) Spearman’s correlation between Faecalibacterium prausnitzii and CD4⁺ T-cell counts among all HIV-1 patients. (D) Spearman’s correlation between unclassified Subdoligranulum sp. and CD4⁺ T-cell counts among all HIV-1 patients. (E) Relative abundance of the two species in the subgroup of VU group based on the CD4+ T-cell counts. (F) Spearman’s correlation between unclassified Subdoligranulum sp. and CD8⁺HLA-DR⁺ T-cell counts and ratio in the IR and INR groups. Blue: correlation between unclassified Subdoligranulum sp. and CD8⁺HLA-DR⁺ T-cell counts; Red: correlation between unclassified Subdoligranulum sp. and CD8⁺HLA-DR⁺ T-cell ratio. (G) Spearman’s correlation between C. comes and CD8⁺HLA-DR⁺ T-cell counts and ratio in the IR and INR groups. Blue: correlation between C. comes and CD8⁺HLA-DR⁺ T-cell counts; Red: correlation between C. comes and CD8⁺HLA-DR⁺ T-cell ratio.

FIGURE 3

Heatmap and hierarchical clustering of pathways enriched or decreased between any of the two groups. Red: higher in the former group; blue: higher in the latter group. ^∗FDR < 0.1. Pathway annotation marked in yellow (amino acid biosynthesis), green (fatty acid biosynthesis), blue (vitamin biosynthesis), red (carbohydrates biosynthesis), and purple (fermentation).