Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection

Journal of Infectious Diseases, Mar 2011

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.

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Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection

A e Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection Netanya G. Sandler Handan Wand Annelys Roque Matthew Law Martha C. Nason Daniel E. Nixon Court Pedersen Kiat Ruxrungtham Sharon R. Lewin Sean Emery James D. Neaton Jason M. Brenchley Steven G. Deeks Irini Sereti Daniel C. Douek for the INSIGHT SMART Study Group 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, CD41 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. - Immune activation is a strong predictor of disease progression in human immunodeficiency virus (HIV) infection. Increases in T cell turnover [1], frequencies of activated T and B cells [2], and serum levels of proinflammatory cytokines and chemokines have been described [3]. A higher frequency or level of CD381 expression on CD81 T cells [4, 5] predicts a faster decrease of CD41 T cells, and higher frequencies of CD381HLA-DR1 CD41 and CD81 T cells predict reduced recovery of CD41 T cells after initiating ART [6]. Higher CD381 expression on CD41 and CD81 T cells predicts shorter survival, independent of plasma HIV RNA levels [7]. Collectively, these observations indicate that immune activation is a critical component of HIV disease pathogenesis. The causes of HIV-associated immune activation remain unclear but are likely multifactorial, including expansion of HIV-specific T cells, reactivity of innate immune cells to HIV-encoded Toll-like receptor (TLR) ligands, loss of immunoregulatory cells, and increased prevalence of other chronic infections [8]. Rapid depletion of CD41 T cells from the intestine [9, 10], decreased luminal immunoglobulin (Ig) A concentration [11], massive enterocyte apoptosis, and breakdown of enterocyte tight junctions [12, 13] result in a compromised intestinal mucosal barrier. Subsequent translocation of microbial products, such as lipopolysaccharide (LPS) and 16S ribosomal DNA (16S rDNA), contributes to immune activation. LPS, a component of the cell wall of gramnegative bacteria, binds membrane or soluble CD14 (sCD14) and the myeloid differentiation-2 (MD-2)-TLR4 complex, resulting in NF-jb activation and production of IL-6, IL-1b, TNF and type I interferons [14–16]. In HIV disease, both LPS and 16S rDNA correlate with systemic immune activation, increased frequencies of CD381HLA-DR1 CD81 T cells, and elevated interferon a levels in the plasma [17, 18]. A potential causal link between HIV-associated inflammation and disease progression was shown in a randomized clinical trial of continuous versus intermittent antiretroviral therapy (the SMART study). HIV-infected persons were randomized to continuous antiretroviral therapy (ART) or CD41 T cell count– driven ART. Subjects randomized to the second arm had a higher risk of morbidity and mortality than did those in the first [19]. ART interruption resulted in a rapid increase in inflammation- and coagulation-associated biomarkers that were associated with increased risks of death, AIDS, and cardiovascular disease (CVD) [20–22]. The mechanism linking HIV replication to inflammation, coagulopathy, and disease progression remains largely undefined. We hypothesized that markers of microbial translocation and its consequences would be associated with death, AIDS, and CVD. In this large cohort of HIV-infected subjects with high CD41 T cell counts and diverse treatment histories, we explored the relationship of enterocyte damage, microbial translocation, and LPS-mediated monocyte activation with these outcomes. MATERIALS AND METHODS Study Design Details of the (...truncated)


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Netanya G. Sandler, Handan Wand, Annelys Roque, Matthew Law, Martha C. Nason, Daniel E. Nixon, Court Pedersen, Kiat Ruxrungtham, Sharon R. Lewin, Sean Emery, James D. Neaton, Jason M. Brenchley, Steven G. Deeks, Irini Sereti, Daniel C. Douek. Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection, Journal of Infectious Diseases, 2011, pp. 780-790, 203/6, DOI: 10.1093/infdis/jiq118