Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

Abstract

Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.

Figure 1. Sevelamer treatment reduces microbial translocation during early SIVsab infection of PTMs.

(A) Comparison between plasma LPS levels in SIVsab-infected PTMs receiving sevelamer (red) and untreated controls (blue). (B) Comparison between plasma sCD14 levels in SIVsab-infected PTMs receiving sevelamer (red) and untreated controls (blue). The P values were assessed as long-term differences in temporal dynamics and obtained using mixed-effects models.

Figure 2. Impact of sevelamer treatment on the microbial translocation in SIVsab-infected PTMs.

Comparison between the levels of microbial translocation in axillary LNs of SIVsab-infected PTMs receiving sevelamer and untreated controls. Representative images (original magnification, ×50) of the LNs stained for LPS core antigen (brown). Note the extensive accumulation of microbial products within the macrophages located around the subcapsular and medullary sinuses and in the paracortical parenchyma of the lymphatic tissues in untreated controls and that there is almost no increase in the levels of LPS in the LNs of PTMs treated with sevelamer. dpi, day after infection.

Figure 3. Sevelamer treatment during early SIVsab infection of PTMs results in reduction of immune activation, inflammation, and viral replication.

Significant differences were observed between SIVsab-infected PTMs receiving sevelamer (red) and untreated controls (blue) with regard to (A) Ki67 expression by CD4⁺ T cells, (B) Ki67 expression by CD8⁺ T cells, (C) HLA-DR expression by CD8⁺ T cells, (D) HLA-DR expression by CD4⁺ T cells, (E) levels of proinflammatory cytokines (illustrated here by IL-1b), (F) levels of CRP, (G) levels of D-dimer, and (H) viral loads. The P values were assessed as long-term differences in temporal dynamics and obtained using mixed-effects models. vRNA, viral RNA.