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. 2018 Sep;24(9):1313-1316.
doi: 10.1038/s41591-018-0132-5. Epub 2018 Jul 30.

Experimental microbial dysbiosis does not promote disease progression in SIV-infected macaques

Alexandra M Ortiz  1 , Jacob K Flynn  1 , Sarah R DiNapoli  1 , Ivan Vujkovic-Cvijin  2 , Carly E Starke  1 , Stephen H Lai  1 , MacKenzie E Long  1 , Ornella Sortino  1 , Carol L Vinton  1 , Joseph C Mudd  1 , Leslie Johnston  3 , Kathleen Busman-Sahay  3   4 , Yasmine Belkaid  2   5 , Jacob D Estes  3   4   6 , Jason M Brenchley  7
Affiliations

Experimental microbial dysbiosis does not promote disease progression in SIV-infected macaques

Alexandra M Ortiz et al. Nat Med. 2018 Sep.

Abstract

Intestinal microbial dysbiosis has been described in individuals with an HIV-1 infection and may underlie persistent inflammation in chronic infection, thereby contributing to disease progression. Herein, we induced an HIV-1-like intestinal dysbiosis in rhesus macaques (Macaca mulatta) with vancomycin treatment and assessed the contribution of dysbiosis to SIV disease progression. Dysbiotic and control animals had similar disease progression, indicating that intestinal microbial dysbiosis similar to that observed in individuals with HIV is not sufficient to accelerate untreated lentiviral disease progression.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS STATEMENT

The authors have no competing interests as defined by Nature Publishing Group, or other interests that might be perceived to influence the results and/or discussion reported in this article.

Figures

Figure 1
Figure 1. Vancomycin treatment promotes dysbiosis in SIV-infected RMs
(a) Longitudinal study design depicting timepoints for vancomycin treatment, SIV-infection, and specimen sampling. (b) Diversity measures Chao1 (α-diversity; left) and unweighted Unifrac (β-diversity; right) of fecal microbiome in RMs at indicated timepoints. Hinges span 25th–75th percentiles, center denotes mean, and whiskers represent min-to-max values. (c) Krona plots depicting relative frequency of fecal Firmicute subtaxa comprising ≥5% phylum burden at d115 p.i. to the family level. Shown taxa are collapsed to the lowest common taxon. (d) Krona plots depicting relative frequency of Proteobacteria as in c. (e) Cladogram depicting significantly disparate fecal taxa frequencies at d115 p.i. to the level of family where nodes and overlays in red highlight features enriched in control animals and those in green, Vanco animals. Arcs demarcate phyla of interest. (f) PCoA of Unweighted UNIFRAC distances measured at d115 p.i. (g) Fecal short-chain fatty acids at baseline and d198 p.i. Average line represents mean. p-values for comparison between timepoints span timepoints; those for inter-group analysis span compared groups. d198 p.i. mean fold-change +/−SEM from baseline values denoted on graphs. For all timepoints, samples were obtained from n=6 and 7 longitudinally accessed control and vancomycin-treated animals respectively, except for d-56 (n=5 and 7) and d198 (n=6 and 6) in b–f. Sequence reads per animal are an average of 1–2 reads per timepoint as listed in the NCBI SRA (PRJNA417022). Alpha diversity indices represent the mean of 10 iterations of 1000 sequences per sample. Statistical significance of vancomycin effect on α-diversity in b and for inter-group analysis in g determined by unpaired, two-way t-test. Intra-group analysis in g by paired, two-way t-test. Significance of vancomycin effect on fecal β-diversity in b and f assessed by PERMANOVA. Significantly enriched features highlighted in e were identified by LEFSE.
Figure 2
Figure 2. SIV disease progression is unaffected by vancomycin-induced intestinal dysbiosis
(a) IHC Claudin-3 staining in representative colon sections (left) and as mean percent negative epithelial perimeter (epithelial damage; right) at necropsy. (b) Mean, longitudinal circulating CD4+ T-cell counts (left) and RB/Colon CD4+ TM frequencies (right). *denotes p-value between groups at d0 of 0.028 for CD4+ T-cell count and 0.021 for RB %CD4+ T-cells. (c) Mean, longitudinal plasma viral loads (left) and cell-associated viral loads from Colon CD4+ TM at necropsy (right). Samples below the limit of detection reported as open diamonds. *denotes p=0.042 at d28 (d) Mean percent IHC positive E. Coli tissue area from necropsy Colon (lamina propria), MLN, and liver. (e) Mean, longitudinal, circulating sCD14 concentrations. (f) Individual plasma IL-6 concentrations at Baseline and d198 p.i. Average line represents mean. d198 p.i. mean fold-change +/−SEM from baseline values denoted on graphs (g) Mean, longitudinal frequencies of RB/Colon TH17. **denotes p=0.005 between groups at baseline. (h) Mean frequency of Colon NKp44+ ILC3 at necropsy. (i) Survival curve depicting time to death. Samples were longitudinally accessed from n=6 and 7 for control and vancomycin-treated animals respectively, except for: d198 (n=6 and 6); in c, where timepoints ≥d198p.i. depict mean viremia for all surviving animals; in g, at d-68 and d14 (n=6 and 6), d0 (n=5 and 6), d28 (n=3 and 4), and d115 (n=5 and 7); and in h (n=6 and 6). Longitudinal lines represent mean and include ±SEM where individual data points are not shown. Statistical significance between groups assessed by unpaired, two-way t-test. Survival significance in i was assessed by Mantel-Cox.
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