Plasma levels of soluble CD14 independently predict mortality in HIV infection

Abstract

Background: Chronic human immunodeficiency virus (HIV) infection is associated with intestinal permeability and microbial translocation that contributes to systemic immune activation, which is an independent predictor of HIV disease progression. The association of microbial translocation with clinical outcome remains unknown.

Methods: This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples.

Results: Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2-16.1; P<.001), with minimal change after adjustment for inflammatory markers, CD4(+) T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D-dimer.

Conclusions: sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection.

Figure 1.

Increased enterocyte damage and microbial translocation in Strategies for Management of Anti-Retroviral Therapy (SMART) study subjects. Shaded areas represent the 95% confidence interval (CI) for levels observed in healthy, human immunodeficiency virus (HIV)–uninfected volunteers. Some tests were not performed for healthy volunteers because of insufficient plasma volumes. A, lipopolysaccharide (LPS) levels are higher in most SMART subjects, compared with the reference range; n = 420 for HIV-infected, treated subjects with HIV RNA levels ≤ 400 copies/mL; n = 155 for HIV-infected, treated subjects with HIV RNA levels >400 copies/mL; n = 117 for HIV-infected, untreated subjects; n = 67 for HIV-uninfected volunteers. B, soluble CD14 (sCD14) levels are higher than the reference range in most SMART subjects, but treated subjects with HIV suppression have higher sCD14 levels than do untreated subjects; n = 420 for HIV-infected, treated subjects with HIV RNA levels ≤400 copies/mL; n = 155 for HIV-infected, treated subjects with HIV RNA levels >400 copies/mL; n = 117 for HIV-infected, untreated subjects; n = 65 for HIV-uninfected volunteers. C, endotoxin core antibody (EndoCAb) levels are lower in most SMART subjects and are lower in treated subjects than in untreated subjects; n = 419 for HIV-infected, treated subjects with HIV RNA levels ≤400 copies/mL; n = 155 for HIV-infected, treated subjects with HIV RNA levels >400 copies/mL; n = 117 for HIV-infected, untreated subjects; n = 60 for HIV-uninfected volunteers. D, intestinal fatty acid binding protein (I-FABP) levels are increased in most SMART subjects regardless of treatment status. A value of 20 pg/mL, which is the limit of detection, was assigned to subjects and volunteers with I-FABP levels below the limit of detection; n = 417 for HIV-infected, treated subjects with HIV RNA levels <400 copies/mL (61.5% with detectable levels); n = 155 for HIV-infected, treated subjects with HIV RNA levels >400 copies/mL (60.9% with detectable levels); n = 116 for HIV-infected, untreated subjects (62.4% detectable with detectable levels); n = 41 for HIV-uninfected volunteers (26.8% detectable). VL, viral load.