Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection
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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.
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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)