A. Bandera

A. Gori

A. Incontri

D. Mangioni

P. Perseghin

AIR Universita degli studi di Milano

1 S E P T E M B E R
Correspondence
Characterization of Immune
Failure by Monocyte
Activation Phenotypes in HIV-
Infected Patients Receiving
Antiretroviral Therapy
TO THE EDITOR—Wilson et al [1] demon-
strated that, in human immunodeﬁciency
virus (HIV)–infected subjects, levels of
inﬂammatory biomarkers known to be
associated with increased clinical risk
(interleukin 6, D-dimer, high sensitive
reactive-C protein, soluble CD14, and
soluble CD163) are more closely related
to markers of monocyte activation and
migration than to markers of T-cell
activation. These data suggest that mono-
cytes may play a prominent role in chron-
ic and serious non-AIDS events, such as
premature cardiovascular disease and
cancer. Meanwhile, several large cohort
studies have demonstrated that HIV-
infected subjects who do not undergo full
CD4+ T-cell restoration during antiretrovi-
ral therapy (ART) (ie, those with immune
failure [IF]) are at greater risk of develop-
ing these non-AIDS conditions [2–6].
Based on the ﬁndings of Wilson et al
[1], we investigated monocyte activation
phenotypes in a group of patients with
IF, compared with patients who did ob-
tain full CD4+ T-cell recovery with thera-
py (immune success [IS]). We performed
a cross-sectional study in 84 HIV-infected
subjects with current CD4+ T-cell counts
<350/µL (IF; n = 39) or >500/µL (IS; n = 45)
after ≥18 months of ART and with HIV
RNA levels <50 copies/mL for≥12 months.
Peripheral monocyte/macrophage (M/M)
phenotypes (based on CD14 and CD16 sur-
face expression in classic CD14++CD16−,
intermediate CD14++CD16+, and non-
classic CD14+CD16++ monocytes) as well
as speciﬁc surface activation markers (eg,
CD163 and CD11b) were evaluated by
ﬂow cytometry on fresh samples.
Patient demographic characteristics
and immunological ﬁndings are provided
in Table 1. The 2 groups were matched by
both age and CD4+ T-cell nadir. The IF
and IS patient groups did not signi-
ﬁcantly differ by sex, duration of HIV in-
fection, modality of transmission for HIV
infection, Centers for Disease Control
and Prevention stage, length of ART, or
hepatitis B virus infection. The preva-
lence of hepatitis C virus infection was
higher in patients with IF than in those
with IS (38.5% vs 17.8%, respectively;
P < .05). By deﬁnition, patients with IF
displayed lower CD4+ T-cell counts (me-
dian [interquartile range (IQR)] for IF
vs IS, 268 [218–314] vs 663 [550–850]
cells/µL; P < .05). A developmental rela-
tionship between circulating monocyte
subsets (from classic by intermediate to
nonclassic) might be postulated. During
systemic infection and under proinﬂam-
matory stimuli, there is an increase ﬁrst
of the intermediate cells followed by the
nonclassic CD14+CD16++ monocytes [7].
We found that, compared with patients
with IS, those with IF showed lower levels
of classic and higher levels of intermedi-
ate monocytes (CD14++CD16−, 82.5% of
total CD14+ [IQR, 77.0%–86.5%] for IF
vs 84.5% [79.8%–88.3%] for IS [P = .05];
CD14++CD16+, 4.6% of total CD14+ [3.2%–
6.2%] vs 4.0% [2.5%–5.1%] [P= .04]). Pro-
portions of nonclassic monocytes were
also higher in patients with IF, although
this difference did not reach statistical
signiﬁcance (CD14+CD16++, 6.7% of to-
tal CD14+ [4.5%–9.6%] for IF vs 5.6%
[3.3%–9.0%] for IS).
CD163 is a haptoglobin-hemoglobin
scavenger receptor expressed by monocytes
and macrophages, cleaved from the cell by
proinﬂammatory stimuli and involved as
soluble receptor (soluble CD163) in the
regulation of inﬂammation [8]. Patients
with IF displayed lower expression of
CD163 than those with IS, for both total
and classic monocytes (CD14+CD163+,
89.1% of total CD14+ [IQR, 85.8%–
91.9%] for IF vs 92.5% [88.3%–93.8%]
for IS [P = .02]; CD14++CD16−CD163+,
79.9% of CD14++CD16− [74.0%–83.2%] vs
83.7% [78.9%–86.9%] [P= .01]). Although
the values were higher in patients with
IF, we found no signiﬁcant differences be-
tween the 2 groups in the proportions of
CD14++CD16+CD163+ (4.3% of CD14++
CD16+ [IQR, 3.0%–6.2%] for IF vs 3.9%
[2.5%–5.1%] for IS; P = .07) or CD14+
CD16++CD163+ monocytes (1.9% of
CD14+CD16++ [0.9%–2.6%] vs 1.2%
[0.6%–2.5%]; P = .35).
CD11b (Mac-1), a member of the β2-
integrin family, is involved in monocyte
adhesion and endothelial transmigration
as well as in macrophage activation.
Constitutively present at low levels on
the cell surface, its expression is increased
after proinﬂammatory stimulation with
cytokines (interleukin 1, tumor necrosis
factor, and interferon γ) and lipopolysac-
charide [9]. The frequency of CD14+
CD11b+ did not differ substantially be-
tween the 2 groups (median, 98.1% of
total CD14+ [IQR, 96.8%–99.1%] for IF vs
97.8% [95.8%–98.8%] for IS; P = .40]). In
contrast, patients with IF showed lower
proportions of CD14++CD16−CD11b+
(82.5% of CD14++CD16− [IQR, 77.0%–
86.5%] for IF vs 84.5% [79.8%–88.3%] for
IS; P < .05) and higher proportions of
CD14++CD16+CD11b+ (4.6% of CD14++
CD16+ [3.2%–6.2%] vs 4.0% [2.5%–
5.1%]; P < .05) monocytes. Levels of non-
classic CD14+CD16++monocytes expressing
CD11b+ did not differ signiﬁcantly between
the 2 groups (6.2% of CD14+CD16++ [IQR,
4.3%–8.9%] for IF vs 4.3% [2.9%–8.1%]
for IS; P = .08). Moreover, we found no
differences in the expression of HLA-DR,
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CD38, or CD69 on M/M between the 2
groups.
We found that suboptimal CD4+ T-cell
recovery during ART in patients with IF
is associated with a shift of M/M pheno-
type from classic toward intermediate
and nonclassic subsets, suggesting a role
of these cells in the systemic immune ac-
tivation typically observed in this group
of patients.
The differential expression of CD163
and CD11b on monocytes observed in IF
compared with IS could suggest a greater
effort by the immune system to deal with
this proinﬂammatory condition. Our ﬁnd-
ings provide further evidence that innate
immune activation contributes to the
pathogenesis of inﬂammation and poor
CD4+ T-cell restoration. Studies focusing
on relationship between monocyte activa-
tion phenotypes and clinical end points
(serious non-AIDS conditions) are indi-
cated to evaluate the prognostic role of
these cellular markers and potential strat-
egies targeting persistent inﬂammation in
the context of viral suppression.
Notes
Financial support. This work was supported
by the Gilead Fellowship Program 2011 and An-
laids Lombardia.
Potential conﬂicts of interest. All authors:
No potential conﬂicts of interest.
All authors have submitted the ICMJE Form
for Disclosure of Potential Conﬂicts of Interest.
Conﬂicts that the editors consider relevant to the
content of the manuscript have been disclosed.
Alessandra Bandera,1 Davide Mangioni,1
Arianna Incontri,2 Paolo Perseghin,2 and
Andrea Gori1
1Division of Infectious Diseases, Department of
Internal Medicine, San Gerardo Hospital, University of
Milan-Bicocca, and 2Apheresis Unit Aferesi e Nuove
Tecnologie Trasfusionali–Transfusion Medicine Service,
San Gerardo Hospital, Monza, Italy
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Table 1. Epidemiological and Viroimmunological Data and Markers of Monocyte Activationa
Data and Markers Immune Failure (n = 39) Immune Success (n = 45) P Valueb
Epidemiological and viroimmunological data
Age, y 51 (46–54.4) 48 (45–52) NS
Male sex, No. (%) 33 (84.6) 38 (84.4) NS
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Abbreviations: ART, antiretroviral therapy; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; NS, not significant
(P > .05).
a Unless identified as No. (%), data represent median (interquartile range) values.
b Statistical analyses were performed using Wilcoxon and χ2 tests.
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Received 4 February 2015; accepted 23 February 2015; elec-
tronically published 19 March 2015.
Correspondence: Alessandra Bandera, MD, PhD, Division of
Infectious Diseases, Department of Internal Medicine, San
Gerardo Hospital, University of Milano-Bicocca, Via Pergolesi
33, 20900 Monza, Italy (a.bandera@hsgerardo.org).
The Journal of Infectious Diseases® 2015;212:839–41
© The Author 2015. Published by Oxford University Press
on behalf of the Infectious Diseases Society of America. All
rights reserved. For Permissions, please e-mail: journals.
permissions@oup.com.
DOI: 10.1093/infdis/jiv166
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Characterization of immune failure by monocyte activation phenotypes in HIV-infected patients receiving antiretroviral therapy

https://air.unimi.it/retrieve/handle/2434/642647/1222069/jiv166.pdf

Characterization of immune failure by monocyte activation phenotypes in HIV-infected patients receiving antiretroviral therapy

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