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Increased circulating levels of lipopolysaccharide (LPS) have been demonstrated in HIV-1-infected progressors. We investigated the effect of antiretroviral therapy (ART) interruptions on plasma LPS levels.Overall, 77 individuals participated in this study (51 HIV-positive and 26 healthy). Ten out of 51 HIV-positive participants were viremic ART-naive patients and 41 out of 51 were chronically suppressed patients on ART (three or more drugs, CD4 cell count more than 400 cells/μl, HIV-1 RNA less than 500 copies/ml for more than 8 months, less than 50 copies/ml at recruitment) undergoing therapy interruption. The limulus amebocyte assay was used to measure plasma LPS levels; enzyme-linked immunosorbent assay to measure plasma levels of endotoxin-core antibodies (EndoCAb), soluble (s)CD14, LPS-binding protein and IFN-α; immunoblotting to measure plasma gelsolin levels; and same day whole blood flow cytometry to measure levels of T-cell-activation markers (CD8+/CD38+, CD8+/HLA-DR+ and CD3+/CD95+).Increases in viremia and T-cell-activation markers were observed during therapy interruptions. During short-term therapy interruptions of less than 12 weeks, no change in LPS levels was found, whereas negative associations between viral load and LPS levels (Spearman's Rho = −0.612, P = 0.0152), viral load and EndoCAb change (ΔEndoCAb, correlation = −0.502, P = 0.0204), and between ΔLPS and ΔEndoCAb (correlation = −0.851, P = 0.0073) were observed. In contrast, increased LPS (P = 0.0171) and sCD14 (P < 0.0001) levels were observed during long-term therapy interruption of more than 12 weeks compared with levels during ART, together with no association between LPS and viral load or EndoCAb. No association between immune activation and LPS was evident at any time point.Increased plasma LPS levels were observed only after more than 12 weeks of ART interruption, despite presence of LPS-controlling host mechanisms.