Vih y paciente septico

www.thelancet.com/infection Vol 15 January 2015 95
Review
The effect of HIV infection on the host response to
bacterial sepsis
Michaëla A M Huson, Martin P Grobusch, Tom van der Poll
Bacterial sepsis is an important cause of morbidity and mortality in patients with HIV. HIV causes increased
susceptibility to invasive infections and affects sepsis pathogenesis caused by pre-existing activation and exhaustion
of the immune system. We review the effect of HIV on different components of immune responses implicated in
bacterial sepsis, and possible mechanisms underlying the increased risk of invasive bacterial infections. We focus
on pattern recognition receptors and innate cellular responses, cytokines, lymphocytes, coagulation, and the
complement system. A combination of factors causes increased susceptibility to infection and can contribute to a
disturbed immune response during a septic event in patients with HIV. HIV-induced perturbations of the immune
system depend on stage of infection and are only in part restored by combination antiretroviral therapy. Immuno-
modulatory treatments currently under development for sepsis might be particularly beneficial to patients with
HIV co-infection because many pathogenic mechanisms in HIV and sepsis overlap.
Introduction
People infected with HIV are at increased risk of
developing other infections. Reports from developed
countries show that, with the introduction of
combination antiretroviral therapy (cART), the incidence
of opportunistic infections such as Pneumocystis jirovecii
pneumonia has decreased substantially, and sepsis is
now the principal cause of intensive care unit (ICU)
admission and death in patients with HIV who are
admitted to hospital.1
Worldwide, patients with HIV are
at increased risk of developing bacterial bloodstream
infections, particularly with non-typhoidal salmonella
(NTS) and Streptococcus pneumoniae,2,3
even in those
using effective cART.4
In developing regions with high
rates of HIV infection, the scale of the problem is
immense. In African hospitals, 31–83% of patients
presenting with fever are infected with HIV, and 10–32%
of these patients have bacterial bloodstream infections,
with mortality rates of 25–46% (table 1).5-15
However, little
is known about the particularities of the host response
during bacterial sepsis in patients with HIV. The
immune response during sepsis is thought to be an
imbalance between proinflammatory and anti-
inflammatory effects, which result in organ failure.16,17
Likewise, HIV infection is characterised by a
combination of immune suppression and chronic
inflammation, which results in exhaustion of the
immune system.18
In this Review we describe how
different components of the immune response might be
affected by HIV during bacterial sepsis, and possible
mechanisms for the increased risk of invasive bacterial
infections. We also discuss parallels in immuno-
modulatory therapies proposed for sepsis and HIV,
which represent an appealing area for future research.
First line defences
Overview
A sepsis event typically starts with a pathogen invading
a normally sterile site. The first line of defence consists
of epithelial cells of the skin, gut, and lungs. After
breaching the epithelial barrier, pathogens are first
detected by innate immune cells, including monocytes,
macrophages, dendritic cells, and neutrophils.19
These
cells express pattern recognition receptors (PRRs) on
their surface and in the cytosol to enable recognition of
conserved motifs expressed by pathogens.20,21
Four
classes of PRRs have been identified: toll-like receptors
(TLRs), C-type lectin receptors (CLRs), nucleotide-
binding oligomerisation domain leucine-rich-repeat
containing receptors (NOD-LRRs), and retinoic acid-
inducible gene I protein helicase receptors (RLRs).20
In
the context of sepsis pathogenesis, TLRs have been
studied the most extensively. They are expressed on the
cell surface (TLRs 1, 2, 4, 5, and 6) to enable recognition
of bacterial outer membrane components, and in
intracellular compartments (TLRs 3, 7, 8, and 9) for
detection of nucleic acids derived from intracellular
pathogens, mainly viruses.20
For bacterial recognition,
TLRs 2, 4, 5, and 9 are the most important. Additionally,
TLR7 can sense bacterial RNA released within
phagosomal vacuoles,22
and TLR3 can function as an
amplifier of host RNA-triggered inflammation during
sepsis.23
Ligand recognition by TLRs triggers a
signalling cascade, which results in the production of
cytokines.20
Although essential for pathogen recognition
and the innate immune response, uncontrolled
stimulation causes excessive inflammation; hence TLR
signalling is normally tightly regulated.
Innate immune cells have several specific functions in
antibacterial immunity. Monocytes and macrophages
have a crucial role in maintaining homoeostasis by
phagocytosis of apoptotic cells and microorganisms.19
As the main producers of proinflammatory cytokines,
they are also thought to be key in sepsis pathogenesis.19
Dendritic cells are the main antigen-presenting cells;
maturation is induced after ingestion of antigen,
followed by migration to lymphoid tissue. Mature
dendritic cells express co-stimulatory molecules on
their surface, which synergise with antigen to activate
T cells.24
Natural killer (NK) cells are implicated in
Lancet Infect Dis 2015;
15: 95–108
Published Online
October 20, 2014
http://dx.doi.org/10.1016/
S1473-3099(14)70917-X
Division of Infectious Diseases,
Centre of Experimental and
Molecular Medicine
(M A M Huson MD,
ProfT van der Poll MD); and
Division of Infectious Diseases,
Centre ofTropical Medicine and
Travel Medicine, Academic
Medical Centre, University of
Amsterdam, Amsterdam,
Netherlands
(Prof M P Grobusch MD)
Correspondence to:
Dr Michaëla A M Huson,
Academic Medical Centre,
University of Amsterdam,
Amsterdam 1105 AZ,
Netherlands
m.a.huson@amc.uva.nl

96 www.thelancet.com/infection Vol 15 January 2015
Review
antibacterial immune responses through the ability to
directly lyse infected cells, provide early sources of
proinflammatory cytokines, predominantly inter-
feron-γ, induce dendritic cell maturation, and amplify
the proinflammatory effects of myeloid cells.25,26
Likewise, natural killer T cells (NK T cells), a subset that
shares cell-surface proteins with conventional T cells
and NK cells, have been implicated in sepsis
pathogenesis because of their strong proinflammatory
cytokine release.27
Recruited neutrophils form an
additional important first line of defence against
invading pathogens. They kill microbes through
phagocytosis, the release of lytic enzymes from their
granules, the production of reactive oxygen inter-
mediates, and the formation of neutrophil extracellular
traps (NETs)—lattices of chromatin decorated with anti-
microbial proteins with strong bactericidal capacity.28
The innate immune system is thought to be mostly
responsible for the excessive release of proinflammatory
cytokines early in sepsis pathogenesis.29
The most
extensively studied proinflammatory cytokines in
sepsis are tumour necrosis factor α (TNFα) and
interleukin 1β, both of which are capable of activating
target cells and induce the production of more
inflammatory mediators.29
Additionally, host cells
release damage-associated molecular patterns (DAMPs)
in response to pathogens or injury, which are recognised
by PRRs, thereby enhancing immune activation. The
most investigated DAMP is HMGB1, which signals via
TLR2, TLR4, and TLR9 to induce cytokine release,
activation of coagulation, and neutrophil recruitment.30
Proinflammatory cytokines and DAMPs seem to have a
double role in sepsis pathogenesis; they are essential
for an adequate innate defence during early stage
infection, but also contribute to hyperinflammation
during late phase uncontrolled infection.20,21
In patients
with severe sepsis and in murine sepsis models, high
concentrations of interleukins 1, 6, 8, and 17, CCL2,
CSF3, and HMGB1 are associated with mortality.29
HIV affects the first lines of defence in several ways.
First, defects of epithelial barriers are common and
have been particularly well described for the gut. In the
gut, HIV causes barrier defects during acute infection,
which are maintained during chronic infection, thereby
enabling invasive infections by intestinal pathogens
such as non-typhoidal salmonella.31
Furthermore,
microbial products that translocate into the circulation
fuel chronic immune activation and exhaustion.32
Toll-like receptors
HIV infection and AIDS are associated with increased
TLR2, TLR3, TLR4, TLR7, and TLR9 expression on
various cells, including T lymphocytes, monocytes,
macrophages, and dendritic cells,33–38
although one study34
reported lower peripheral blood mononuclear cell
(PBMC) RNA expression levels of TLR3, TLR4, and TLR9
in patients with chronic HIV unresponsive to cART.
Reports on the functional effect of differential TLR
expression are inconsistent. Ex-vivo studies with PBMCs
from patients with HIV noted a correlation between
increased expression of TLRs and increased TNFα
production after stimulation with lipopolysaccharide, a
Study location
andtimeframe
Primary
inclusion
criteria
Patients
infectedwith
HIV
(%ofpatients
tested)
CA
bacterial
BSI in
patients
with HIV
(%)
Main isolates in
patientswith
HIV (%)
Mortality in
patients
with HIV
withCA
bacterial BSI
Archibald,
19985
UrbanTanzania,
1995
Febrile
(≥37·5°C)
admission
282 (55%) 51 (18%) NTS (45%),
Escherichiacoli
(14%),
Streptococcus
pneumoniae
(12%)
Not reported
Archibald,
20006
Urban Malawi,
1997
Febrile
(≥37·5°C)
admissions
173 (74%) 37 (21%) Spneumoniae
(57%), NTS
(30%)
Not reported
Arthur,
20017
Urban Kenya,
1988–97
Hospital
admission
436 (32%) 87 (20%) NTS (46%),
Spneumoniae
(33%), Ecoli (6%)
39%
Bell, 20018
Urban Malawi,
1998
Febrile
(37·5°C)
admissions
173 (73%) 36 (21%) NTS (62%), Ecoli
(7%), Salmonella
Typhi (7%)
Not reported
Crump,
20119
RuralTanzania,
2007–08
Febrile
(≥38°C)
admissions
161 (40%) 26 (16%) Spneumoniae
(54%), Ecoli
(12%), NTS (8%),
STyphi (8%)
Not reported
Grant,
199710
Ivory coast,
1995
Admission
tothe
infectious
diseaseunit
198 (79%) 39 (20%) NTS (59%), Ecoli
(15%),
Spneumoniae
(10%)
46%
Mayanja,
201011
RuralUganda,
1996–2007
Fever
(≥38°C)with
no
detectable
malaria
parasites
488 (64%) 152 (31%) Spneumoniae
(43%), NTS
(26%), Ecoli (6%)
Not reported
Meremo,
201212
UrbanTanzania,
2011
Hospital
admission
with fever
(>37·5°C)
156 (45%) 16 (10%) NTS (75%) 35%
Nadjm,
201213
RuralTanzania,
2007
Fever and
one severity
criterion
69 (35%) 12 (17%) NTS (25%),
Spneumoniae
(25%),
Streptococcus
pyogenes (17%)
25%
Peters,
200414
Urban Malawi,
2000
Admission
with fever
(≥37·4°C)or
historyof
fever inthe
past 4days
291 (83%) 66 (23%) NTS (67%),
Spneumoniae
(20%), Ecoli (6%)
Not reported
Ssali,
199815
Uganda, 1997 Admission
with fever
(>38°C)
222 (76%) 33 (15%) Salmonella spp
(39%),
Spneumoniae
(33%)
Not reported
Data was derived from prospective observational studies, which were previously described by Huson and colleagues.3
CA=community acquired. BSI=bloodstream infection. NTS=non-typhoidal salmonella.
Table 1: Burden of community-acquired bacterial bloodstream infections in patients with HIV in African
countries where HIV is highly prevalent

Review
See Online for appendix
TLR4 ligand.36,38
By contrast, alveolar macrophages from
patients with HIV showed a classic activation phenotype
with increased TLR4 expression, although binding,
internalisation, and killing of opsonised S pneumoniae
bacteria, which signal via TLR2, TLR4, and TLR9, were
similar to HIV-negative controls.37
TLR3 and TLR7 are
known to be key modulators in anti-HIV immunity, and
HIV-induced changes in expression of these TLRs might
have a role during antibacterial defence, but no studies
have yet investigated this subject.
Most evidence suggests that upregulation of TLRs is
responsible for cell activation in response to bacteria in
patients with HIV, especially in those with advanced
disease, although functional consequences differ
according to cell type. Increased expression of TLRs on
cytokine-producing cells might contribute to aberrant
inflammation in the disturbed homoeostasis in sepsis,
although this possibility has not yet been addressed in
in-vivo studies.
Monocytes and macrophages
The effect of HIV on monocytes and macrophages is
mainly indirect because only a small percentage of
these cells are infected with HIV.39
HIV-mediated
defects in phagocytosis, cell signalling, and cytokine
production have been described, although results vary
between studies (appendix).
Ex-vivo studies using monocytes or monocyte-derived
macrophages from patients with HIV, reported reduced
phagocytosis of Escherichia coli40
and, in symptomatic
patients with HIV, Staphylococcus aureus.41
By contrast,
others observed normal phagocytic function of
macrophages towards opsonised E coli and S aureus in
vitro,42
and increased monocyte phagocytosis of these
pathogens in cells harvested from patients with early
HIV infection.43
In peripheral blood, both monocytes
and macrophages appear to show an HIV-induced,
primed, proinflammatory state, with increased cytokine
release on stimulation with TLR ligands.44,45
A non-classic
subset of monocytes with high expression of M-DC8, a
subset that is also increased in inflamed tissue in chronic
inflammatory diseases such as rheumatoid arthritis, was
identified as the predominant cell type responsible for
TNFα overproduction46
(table 2).47–67
Several studies also examined the effect of HIV on the
alveolar compartment. Although normal alveolar
Study condition* HIV-induced changes Comments
Whole blood In vivo ↑ Interleukin 6, interleukin 10,TNFα,
interleukin 1α, interleukin 1β, interleukin 8,
CCL2, interleukin 1R1, and interferon γ47,48
↓ interleukin 12, andCSF248,49
Cytokine levels normalised aftertreatmentwith cART47,48
Two studies50,51
examined cytokine levels in sepsis patients, but recorded no
differences, except higher interleukin 10 concentrations in HIV co-infected
patients inoneofthese studies50
DecreasedCSF2 levelswere seen in patientswith HIVwith advanceddisease
Peripheral blood
mononuclear
cells
Ex-vivo and in-
vitro stimulation
↑TNFα 38,46,52
··
Monocytes Ex-vivo
stimulation
↑ Interleukin 6, interleukin 1β,TNFα44
··
M-DC8
monocytes
Ex-vivo
stimulation
↑TNFα46
These cellswere identified asthe main celltype responsible forTNFα
overproduction46
Increased levelsof M-DC8 monocyteswere recorded in viraemic patients
with HIV, but not in virally suppressed patientson cART46
Alveolar
macrophages
Ex-vivo
stimulation
↓TNFα, interleukin 8, interleukin 1253–56
Reports conflictonthis subject;other studies noted increased interleukin 8,
12 and 10 in alveolar macrophagesof patientswith HIV56
Impaired interleukin 12 productionwasonly reported in patientswith
advanceddisease56
Dendritic cells In-vitro and ex-
vivo stimulation
↓ Interleukin 12,57–59
interleukin 6,58
interferon γ,γ,58,6058,60
interferon α,interferon α,59,6159,61
interleukin 2,interleukin 2,6161
and interleukin 10and interleukin 106060
Most reportsdescribedecreased cytokine production after stimulation, but
normal,62
or even increased cytokine responsesto stimulationwere also
reported63
Natural killer
cells
Ex-vivo
stimulation
↓ Interferon γ64
The effectwasobserved in both cART-treated anduntreated patients64
Natural killer
T cells
Ex-vivo
stimulation
↓ Interferon γ and interleukin 465
Stimulationsweredonewith marine sponge-derived α-galactosylceramide
(αGalCer) as a ligand;65
similar studiesusing bacterial ligands as a stimulus
were not available
Cytokine secretionwas restored by cART65
CD4T cells In-vivo ↑ Interleukin 1066
Interleukin 10 productionwas increased in chronic progressors and recently
infected individuals, but not in non-progressorswith HIV66
Gut mucosa
Th17 cells
Ex-vivo
stimulation
↓ Interleukin 22,TNFα, and interferon γ67
↑ Interleukin 1067
Restorationof cytokine responseswas seen after prolongedtreatmentwith
cART67
cART=combination antiretroviral therapy. *All studies are in human beings or used human cells, or human cell lines; all stimulations were done with bacteria or bacterial
products unless otherwise specified.
Table 2: Effect of HIV infection on the cytokine milieu by cell type

Review
macrophage phagocytosis of S pneumoniae was
previously reported,37
a study68
noted impaired phago-
cytosis in HIV-infected small alveolar macrophages, as
well as impaired proteolysis of phagosomes in both
infected and uninfected alveolar macrophages.
Cytokine release, including that of interleukin 8, in
response to S pneumoniae, and TNFα, in response to
TLR2 and TLR4 ligands, was impaired in alveolar
macrophages from patients with HIV (table 2).53–55
Considering the crucial role of TNFα in resisting
experimental S pneumoniae infections in mice,69
and
the established part in neutrophil recruitment to sites
of infection by interleukin 8, a reduced cytokine
response by alveolar macrophages might contribute to
increased susceptibility to invasive pneumococcal
disease in patients with HIV (figure 1). Another study56
noted increased production of both proinflammatory
(interleukin 8 and 12) and anti-inflammatory
(interleukin 10) cytokines by alveolar macrophages of
asymptomatic patients with HIV after stimulation with
S aureus. However, in patients with more advanced
disease interleukin 12 release was reduced after
stimulation, which was mediated by interleukin 10.56
Interleukin 12 is known to induce T-helper (Th) 1
development, which is essential for defence against
intracellular pathogens, such as non-typhoidal
salmonella, but also has a role in the immune response
against S pneumoniae.70
Finally, alveolar macrophage
apoptosis, a critical host cell response for control of
infection, including pneumococcal pneumonia,71
might
be impaired in patients with HIV.72
Most evidence suggests impairment of phagocytosis
by macrophages in individuals with HIV, which is
accompanied by impaired proinflammatory cytokine
release, especially in alveolar macrophages. These
defects might contribute to increased susceptibility to
bacterial infection and deregulated inflammation.
Dendritic cells
In patients with HIV, around 10–15% of dendritic cells
are infected,57
but HIV also affects dendritic cell
function in indirect ways (appendix). Patients with HIV
have reduced peripheral blood dendritic cell
numbers,61,63,73,74
which are inversely correlated to viral
↑S pneumoniae
↓Interleukin 17
↓CD4
T cells ↓Macrophage recruitment
↓Macrophage phagocytosis
↓TNFα
↓Interleukin 8
↓Neutrophil recruitment
Bloodstream invasion of S pneumoniae
Alveolar interstitium
Nasopharyngeal cavity
↓Opsonic capacity of IgA ( ) and IgG ( )
Bloodstream
Alveolar space
Nasopharynx interstitium
Figure 1: Alterations in the host response of patient with HIV that might cause increased susceptibility to invasive infection with Streptococcus pneumoniae
In the upper airways, impaired recruitment of macrophages due to CD4 T-cell depletion and low concentrations of interleukin 17 enable colonisation by
S pneumoniae on the respiratory epithelium. In the lower airways, impaired antipneumococcal activity of IgA and IgG on the mucosal surface of the respiratory
epithelium allows the attachment of S pneumoniae to the epithelial cells and migration of the pathogen across the epithelial barrier. Ineffective opsonisation also
impairs phagocytosis by alveolar macrophages. Furthermore, alveolar macrophages from HIV-positive patients showed decreased TNFα production in response
to TLR2 and TLR4 ligands, and concentrations of TNFα in bronchoalveolar lavage fluid are reduced in patients with HIV, thereby hindering an effective
proinflammatory response. Alveolar macrophages from patients with HIV produce lower concentrations of interleukin 8 in response to S pneumoniae, resulting
in less effective recruitment of neutrophils. Neutrophils of HIV patients are also less able to respond to chemotactic signals, such as interleukin 8, but also
pneumolysin derived from the bacterium, further impairing a massive neutrophil influx. The combination of impairments in antipneumococcal defence enables
the invasion of S pneumoniae into the bloodstream. TNFα=tumour necrosis factor α.

Review
load,74
and positively correlated with CD4 counts.61
Homing of dendritic cells in lymph nodes75
and
increased apoptosis76
are possible explanations.
Reports on the effect of HIV on dendritic cell
maturation are inconsistent. An atypical phenotype of
immune activation without full maturation has been
reported,56,77
as well as reduced capacity to mature in
response to stimuli combined with interleukin 10
induction and immune suppression.78
By contrast,
normal maturation in response to stimuli57,73
and HIV-
induced maturation have also been described.79
Stimulation-induced production of cytokines,
including interleukin 12,57–59
interleukin 6,58
interferon
γ,58,59
interferon α,59,61
interleukin 2,60
and interleukin
10,60
was impaired by HIV, as well as dendritic cell-
mediated activation of T cells (table 2).79
Reduced
interleukin 12 production was associated with impaired
activation of NK cells in vitro.59
Some studies, however,
reported normal62
or even increased cytokine responses
of dendritic cells to stimuli.63
The number of dendritic cells in peripheral blood is
reduced in patients with HIV, and, additionally, most
studies report impaired dendritic cell function. HIV-
induced tolerance to antigen and reduced maturation
of dendritic cells might compromise immunity against
various of pathogens, rendering patients with HIV
more susceptible to sepsis.
NK cells and NK T cells
Reduced NK cell numbers and function during HIV
infection contribute to decreased resistance against
HIV and other pathogens (appendix).80,81
Ex-vivo
stimulation of NK cells from patients infected with HIV
with E coli or Salmonella typhimurium showed that both
untreated and treated patients had lower overall
frequencies of responsive interferon-γ-producing NK
cells (table 2).64
Although this study is the only one to
specifically address antibacterial immune responses by
NK cells from patients with HIV, many studies report
on HIV-induced changes that prevent an effective anti-
HIV NK cell response, which might also result in
impaired antibacterial defence. First, correlating with
viral load, HIV infection induces expansion of a CD56-
negative NK cell subpopulation, which is unresponsive
to stimulation and is thought to represent an exhausted
state, with concomitant loss of responsive CD56-
positive NK cell subsets due to increased apoptosis.80,82
CD56-negative NK cells are also defective in their
interaction with dendritic cells, thereby contributing to
the accumulation of immature dendritic cells.80,83
Second, HIV causes shedding of MHC class I chain-
related molecules MICA and MICB from the surface of
infected cells. By binding to the NK cell receptor
NKG2D, soluble MICA and MICB provide a negative
feedback signal, resulting in subsequent down-
regulation of NKG2D, thereby promoting the
generation of anergic NK cells.82
Third, decreased
production of chemokines impairs chemotactic
signalling to other immune cells.80,84
NK cells from
patients with HIV also showed increased expression of
NK-cell inhibitory receptors that prevent lysis of
target cells, but these effects were reversed in virally
suppressed patients on cART.85,86
No studies on NK
T-cell antibacterial defence in HIV-infected hosts were
identified, but selective NK T-cell depletion might
hinder the proinflammatory response to bacterial
pathogens.65
Various mechanisms contribute to expansion of an
anergic NK cell population that is less capable of
responding to pathogens in individuals with HIV. This
expansion might impair direct NK-cell mediated
defence against bacteria, and compromise crosstalk
with other immune cells.
Neutrophils
In patients with HIV infection, neutrophils might not
be able to function effectively because of several
mechanisms (appendix). First, neutropenia is common
in patients with HIV.87
Possible mechanisms include
increased apoptosis due to the presence of auto-
antibodies,88
activation in the absence of secondary
infection,89
reduced production attributed to decreased
levels of CSF3,90
and treatment-induced neutropenia.49
Additionally, defects in neutrophil function have been
described in patients with HIV, including reduced
chemotaxis,91,92
impaired transepithelial migration93
(possibly explained by reduced expression of
interleukin 8 receptors on neutrophils of these
patients92
), and impaired phagocytosis.40,94–96
In one
study96
phagocytosis of S aureus was only impaired
when neutrophils were incubated with serum of
patients with HIV, indicating reduced opsonisation
with antibodies as the mechanism underlying defective
phagocytosis. However, in other investigations,94,95
decreased phagocytosis was observed after previous
opsonisation in healthy serum, suggesting an antibody-
independent mechanism. Although the aforementioned
studies used neutrophils from patients with HIV with
advanced disease, one study43
recorded an increased
capacity for neutrophils to phagocytose E coli and
S aureus from patients with early HIV infection.
Superoxide production, a mechanism of microbial
killing, was increased in unstimulated neutrophils
from patients with HIV,43
but the response to pathogens,
such as E coli, was reduced.40,89
Additionally, HIV causes
impaired C5a (a complement constituent with
proinflammatory properties) and interleukin-8-induced
degranulation,97
which is associated with reduced
expression of C5a and interleukin 8 receptors.92,97
Although HIV causes NET release from neutrophils, it
can also counteract this response by inducing
production of interleukin 10 by dendritic cells to inhibit
NET formation.98
Hence, HIV-induced inhibition of
NET formation in response to bacterial pathogens

Review
could impair effective host defence. Finally, ex-vivo
bacterial killing was reduced,96
especially in patients
with advanced disease.96
However, one study94
reported
normal killing of S aureus by neutrophils from patients
with AIDS.
HIV-related defects in neutrophil numbers, chemo-
taxis, phagocytosis, superoxide production, cytokine
release, bacterial killing, and NET formation have been
described, suggesting that HIV renders the host more
susceptible to bacterial infection, at least in part by
impairing neutrophil-mediated host defence.
Cytokines and DAMPs
Abundant evidence suggests a change in cytokine
profiles in patients with HIV, although very few studies
have investigated this change in the context of sepsis
(table 2). Two studies50,51
provided comparative data for
inflammatory parameters in patients with sepsis
admitted to the ICU with or without HIV co-infection.
A wide range of cytokines were measured, but no
significant differences were noted for most of them. In
one study, high concentrations of interleukin 10 were
reported in HIV-positive patients compared with HIV-
negative patients, which was associated with increased
mortality.50
However, the HIV-negative septic controls
differed substantially in age and site of infection, which
complicates interpretation of these results.50,51
Studies47,99
using plasma from patients with HIV but
without sepsis reported increased concentrations of
several cytokines implicated in sepsis pathogenesis:
interleukin 6, interleukin 10, TNFα, interleukin 1A,
interleukin 1β, interleukin 8, CCL2, interleukin 1
receptor antagonist, and, in acute HIV infection,
interferon γ. Concentrations of HMGB1 were also
increased in patients with HIV.100
However, circulating
concentrations of the proinflammatory cytokines
interleukin 12, and CSF2, were decreased.49,48
Studies on
the effect of cART noted normalisation of most cytokine
perturbations.47,48
Raised concentrations of circulating inflammatory
markers might in fact be associated with the
development of infection; a correlation was identified
between raised concentrations of C-reactive protein in
patients with HIV and an increased risk of bacterial
pneumonia.101
A possible explanation for raised cytokine con-
centrations is a primed state of immune cells in patients
with HIV causing hyper-responsiveness to stimulation;
for example, by microbial products translocated from
the gut. Increased TNFα production in response to
lipopolysaccharide was observed in PBMCs and
monocytes isolated from patients with HIV.38,46
Decreased interleukin 12 concentrations might relate to
the type of stimulus and stage of disease, with patients
with AIDS showing the most profound deficiency.102
There is abundant evidence for increased circulating
concentrations of both proinflammatory and
anti-inflammatory cytokines in patients with HIV,
combined with ex-vivo evidence for a primed state of
immune cells in response to stimulation, which could
result in a more profound imbalance between these
mediators during sepsis. However, the small number of
studies available50,51
in patients with HIV and sepsis
reported few differences in cytokine concentrations
compared with HIV-negative patients with sepsis.
Lymphocytes
Overview
Antigen-presenting cells interact with lymphocytes to
initiate the adaptive immune response. In response to
the presentation of antigen, effector CD4 T cells secrete
cytokines, such as interferon γ, to enhance phagocytic
killing and interaction with B cells to initiate production
of antibodies.19
B cells are the cornerstone of immuno-
logical memory, and represent the main defence
mechanism against reinfection. B cells have also been
shown to have an important role in the enhancement of
innate immune responses during bacterial sepsis.103
Sepsis causes a substantial depletion of CD4, CD8, and
B lymphocytes because of increased apoptosis, which is
correlated with sepsis severity.17,104
Because T cells are
important in coordinating innate immunity, increased
apoptosis of T cells might hinder the proinflammatory
response.104
Remaining lymphocytes also show
significant reductions in cytokine release on
stimulation.105
T lymphocytes
During HIV infection, both T-cell numbers and
function become compromised (appendix). CD4 T-cell
depletion develops through various mechanisms,
including direct virus-induced killing, induction of
apoptosis, and an inability of the thymus to efficiently
compensate for the lost T cells.106
In addition to
depletion of CD4 T cells, HIV downregulates the CD4
receptor, which might reduce the immune functions of
surviving cells.107
Of particular relevance in the context
of sepsis, patients with HIV displayed increased
apoptosis of CD3 T cells after in-vitro challenge with
S pneumoniae.108
A particular subset of CD4 cells, Th17
cells, which predominate in the gastrointestinal tract
and are important in antibacterial defence, are
substantially depleted,109
and remaining Th17 cells have
an enahanced interleukin 10:TNFα ratio, suggestive of
an anti-inflammatory phenotype (table 2).67
Similarly,
increased interleukin 10 production was identified in
peripheral blood CD4 T cells.66
Mucosal-associated
invariant T cells (MAIT cells), a subset of innate-like,
tissue-infiltrating lymphocytes that produce
interleukin 17, interleukin 22, interferon γ, and TNFα,
were also shown to be severely depleted in blood of
patients with HIV, and remaining cells showed an
activated phenotype combined with functional
exhaustion.110,111
Although numbers of MAIT cells in the

Review
gut were relatively preserved in these studies,110,111
a
third study reported MAIT cell depletion in the colon of
patients with HIV.112
Since MAIT cells are known to be
activated by a wide range of bacteria and fungi,113
their
depletion might have an important role in increased
susceptibility of patients with HIV to bacterial sepsis.
Mucosal depletion of interleukin-17-producing cells,
like TH17 cells and MAIT cells, might be related to
increased risk of patients with HIV developing non-
typhoidal salmonella bacteraemia, because interleukin
17 is known to have an important role in host defence
against dissemination of enteric pathogens (figure 2).114
Additionally, interleukin-17-producing CD4 T cells were
shown to be essential for recruitment of monocytes and
macrophages to allow for effective pneumococcal
clearance from the nasopharynx,115
suggesting that CD4
cell depletion has a role in the vulnerability of patients
with HIV to the invasive pneumococcal infections
(figure 1).
Although CD4 T-cell counts decrease, CD8 T-cell
numbers expand during HIV infection.116
Nonetheless,
both T-cell compartments display a phenotype of
immune activation and exhaustion, as suggested by
heightened expression of the activation markers HLA-
DR and CD38, and of the inhibitory receptors PDCD1
and CTLA4 in untreated patients with HIV.117,118
Furthermore, the CD8 T-cell compartment has been
shown to arrest at a late differentiated phenotype,119
and
is unable to mount an effective cytolytic response.120,121
Both reduction in CD4 T-cell numbers, and functional
impairments of CD4 T cells and CD8 T cells might
contribute to increased susceptibility of patients with
HIV to develop invasive bacterial infections and sepsis.
Most of these defects can be restored by cART,106
but
impaired restoration of the CD4 T-cell proliferation
response has been described in patients with HIV with
lower nadir CD4 T-cell counts before therapy,122
thus
providing one possible explanation for higher rates of
bacteraemia in cART-treated patients compared with
HIV-negative people.
B-lymphocytes
In patients with HIV, several defects in B-cell function
have been detected, which could have a role in increased
susceptibility to infections, especially in patients with
non-typhoidal salmonella and S pneumoniae (appendix).
Functional disturbances include hypergammaglo-
bulinaemia, polyclonal activation and exhaustion,
impaired class-switch recombination, dysfunctional
interaction between T cells and B cells, blunted
proliferation response to both T-cell-dependent and
T-cell-independent antigens, poor immune responses
against vaccination antigens, short duration of antibody
response induced by pneumococcal vaccination, and
increased apoptosis.123–127
Additionally, patients with HIV show changes in the
distribution of B-cell subsets. Resting memory B cells
are severely depleted, whereas transitional B cells are
expanded.123
An aberrant B-cell population,
CD21low
CD27−
B cells, normally present in very low
numbers in peripheral blood, was reported to rise in
the blood of viraemic patients with HIV proportional to
viral load,128
which showed features of immune
activation and cellular exhaustion.129
Although changes
in most B-cell subtypes are restored by cART, resting
memory B cells usually remain depleted128
because they
can only be preserved when cART is started early in
infection.130
Additionally, IgG concentrations were
shown to remain raised despite long-term cART in 45%
of patients, indicating continuous B-cell activation.131
B-cell dysfunction probably has an important role in
the increased risk of patients with HIV developing
invasive infections with S pneumoniae (figure 1) and
non-typhoidal salmonella (figure 2). Patients with HIV
have reduced numbers of pneumococcal antigen-
specific IgG antibody-secreting cells and lower
concentrations of pneumococcal antibodies.124,132
Additionally, IgA in the epithelial lining fluid of the
lung showed impaired antipneumococcal activity.133
Although some studies reported normal,134
or even
Th17
↓Interleukin 17
Intestinal lumen
Lamina
propria
Bloodstream
Interleukin 17
NTS in the gut
of a host without
HIV infection
NTS in the
gut of an
HIV-infected
host
Th17 depletion
and reduced
interleukin 17
compromise
gut barrier
function
Inhibitory
antibodies bind
to LPS, which
prevents
bacterial killing
Binding of
IgG to outer
membrane
proteins
enables
bacterial lysis
and killing
C1q
LPS
MAC
Figure2: HIV-induced changes in host defence against non-typhoidal salmonella (NTS) infection fromthe gut
Normally, interleukin-17-producing Th17 cells effectively prevent invasion of NTS from the gut (left side), but
HIV infection results in Th17 cell depletion and reduced interleukin 17 concentrations, thereby compromising
the gut barrier function against NTS (right side). If NTS bacteria manage to reach the bloodstream in a host
without HIV infection, they are effectively opsonised by IgG antibodies that bind to the outer membrane
protein of NTS and enable complement (C1q) binding, followed by formation of a MAC on the bacterial surface,
resulting in lysis and killing of the bacteria (left side). By contrast, in the patient with HIV, NTS bacteria are
opsonised by antibodies that have an inhibitory effect on bacterial killing. They do not bind to the outer
membrane protein of the NTS, but to its LPS, which does not enable lysis and killing, and allows for survival of
NTS in the bloodstream (right side). NTS=non-typhoid salmonella. MAC=membrane attack complex.
LPS=lipopolysaccharide.

Review
increased concentrations of IgG anti-pneumococcal-
specific antibodies in patients with HIV,135
the opsonic
capacity of these antibodies was reduced.135
In the case
of NTS, IgG hypersecretion might be implicated in the
increased risk of infection in patients with HIV; serum
from African patients with HIV contained high
concentrations of IgG antibodies against non-typhoidal
salmonella that prevented destruction of Salmonella
spp.136
These antibodies had non-neutralising activity
against non-typhoidal salmonella lipopolysaccharide
and exerted a dose-dependent inhibitory effect on the
killing capacity of healthy serum, suggesting an
important role for anti-salmonella LPS IgG in the
prevention of clearance of non-typhoidal salmonella in
patients with HIV (figure 2).137
Perturbations in humoral immunity probably have a
substantial role in the increased susceptibility of
patients with HIV to bacterial infections, with
simultaneous depletion of the memory B-cell com-
partment, and inadequate activation, IgG production,
and B-cell exhaustion, which are only partly restored by
cART.
The coagulation system
Patients with sepsis invariably show a disturbed balance
between coagulation and anticoagulation.16,19
In severe
cases, this disturbance results in disseminated intra-
vascular coagulation, while at the same time, a
consumptive coagulopathy develops, causing increased
risk of bleeding. disseminated intravascular coagulation
is triggered by a fulminant host response to infection,
causing aberrant expression of tissue factor, impairment
of physiological anticoagulant pathways due to
endothelial dysfunction, and the suppression of
fibrinolysis due to overproduction of SERPINE1 by
endothelial cells.16
Several abnormalities in the coagulation system and
endothelial cell function of patients with HIV have
been identified (figure 3). In general, HIV-induced
alterations in haemostasis are remarkably similar to
those described in sepsis. First, patients with HIV
display a procoagulant state, as shown by their
increased risk of thromboembolic events.137
Coagulation
activation in these patients is further suggested by
increased concentrations of D-dimer and fibrinogen,138,139
increased platelet activation,140
and increased expression
of tissue factor on platelets and monocytes.141,142
Anticoagulation is hindered by reduced concentrations
of protein C, and protein S,138,143
and fibrinolysis might
be impaired as a consequence of increased SERPINE
concentrations in patients with HIV.139,143
Last, ample
evidence shows endothelial activation and dysfunction
in patients with HIV. Raised concentrations of VWF,
soluble ICAM1, and soluble VCAM1 have been reported
in several studies.138,143,144
Additionally, endothelial
function, assessed by measuring flow-mediated dilation
of the brachial artery, was impaired in patients with
HIV.145
Autopsy studies of patients with HIV, with or
without AIDS-related complications, also reported
endothelial injury.146,147
Finally, a study on angiogenic
factors in severe bacterial infection in Malawian
children noted that HIV-positive cases had significantly
higher concentrations of ANGPT2 compared with HIV-
negative children with similar illness.148
High con-
centrations of ANGPT2, an angiogenic peptide that
increases endothelial activation and vascular
permeability, are associated with disseminated intra-
vascular coagulation and mortality in sepsis.148
Studies
on the effect of cART are inconsistent, with some
recording complete normalisation144
and others
reporting partial improvement,136,149
as well as studies
describing a detrimental effect of cART, especially
regimens containing protease inhibitors.137,150
At present, no studies on the effect of HIV infection
on the procoagulant response to sepsis exist. In view of
the disturbed haemostatic balance in patients with HIV,
with alterations that strongly resemble those detected
in sepsis, it is conceivable that HIV causes an even
greater disruption of procoagulant and anticoagulant
mechanisms during sepsis.
The complement system
The complement system is an important part of the
first-line host defence against bacteria, by opsonisation,
lysis of pathogens and infected cells, and production of
chemoattractants. Clinical and experimental sepsis are
↑ANGPT2
↑sICAM1
↑sVCAM1 ↑VWF
↑Tissue factor
Coagulation cascade
↑Fibrinogen Fibrin
Thrombus formation↑D-dimer
Activated protein C
↓Protein C
↓Protein S
↑SERPINE
↓Fibrinolysis
Increased coagulation Impaired anticoagulation and fibrinolysis
Endothelial activation and damage
Figure3:HIV-inducedchangesinthecoagulationsystemandendotheliumresemblesepsis-inducedcoagulopathy
Expression of tissue factor on circulating monocytes is increased in patients with HIV, which triggers the
extrinsic pathway of the coagulation cascade, eventually resulting in the transformation of fibrinogen to fibrin.
Increased concentrations of fibrinogen and D-dimer, a fibrin degradation product, are seen in patients with HIV,
providing further evidence for coagulation activation. The coagulation cascade is normally balanced by the
anticoagulant system, which includes activated protein C. However, in patients with HIV protein C, and protein
S, which is needed to activate protein C, are depleted. Additionally, fibrinolysis is inhibited by increased
concentrations of SERPINE, further facilitating thrombus formation in patient with HIV. The endothelium of
patients with HIV becomes activated and damaged. Secretion of sICAM1, sVCAM1, and VWF are increased, and
the endothelium shows an irregular pattern with multinucleated endothelial cells and increased monocyte
adhesion. Higher concentrations of ANGPT2 are also seen in patients with HIV,and are known to cause
endothelial cell death and disrupt the endothelial monolayer. Notably, all these changes are very similar to those
described in patients with sepsis. sICAM-1=soluble ICAM1. sVCAM1=soluble VCAM1.

Review
associated with activation of the complement system,
as shown by increased plasma concentrations of com-
plement constituents C3a, C4a, and C5a.21
Although
complement is essential in the host defence against
bacteria, increased circulating C3a and C5a are likely to
contribute to sepsis-induced tissue damage, multiorgan
failure, and septic shock, because of their strong
proinflammatory functions.151
C5a is important for the
outcome of experimental sepsis, as reported by studies
in which treatment with an anti-C5a antibody improved
haemodynamic parameters, attenuated coagulopathy,
and improved organ function.21
Although the complement system is generally known
for its activity against bacterial pathogens, many reports
describe HIV-induced activation of the complement
system through the the classic pathway via interaction
of gp41 with C1q;152
interaction of HIV with mannose-
binding lectin, the triggering molecule of the lectin
pathway;152
and activation of the alternative pathway
through C3 binding of HIV-infected monocytes and
lymphocytes.153
After seroconversion, HIV-specific
antibodies further enhance complement activation via
the classic pathway,152
and raised concentrations of
circulating C5a have been recorded in patients with
HIV.91
However, HIV can escape complement-induced
lysis by acquiring regulators of complement activation,
which allow the virus to use the complement system for
transport to the lymphoid system and infection of
susceptible cells.152
Increased complement activation might contribute to
the generalised immune activation observed in HIV
and, hypothetically, have a detrimental role during
sepsis pathogenesis by disturbing the balance between
proinflammatory and anti-inflammatory mechanisms.
However, at present, studies investigating the effect of
HIV infection on complement activation in sepsis have
not been reported.
Future perspectives
The present treatment of sepsis is based on antibiotics
and supportive care.154
In past decades, many clinical
trials have been done to investigate inhibition of the
abundant inflammatory response generally held
responsible for sepsis mortality.19,21
In more recent
years, however, attention has shifted to findings that
patients with sepsis invariably show evidence for
immune suppression, which has been implicated as an
important cause of secondary infections and late
mortality.17
Preclinical studies have suggested that
immune stimulatory therapy, which aims to overcome
sepsis-induced immune suppression, could improve
sepsis outcome. Interventions assessed in this context
include immunomodulatory cytokines, such as
interleukin 7, interleukin 15, and CSF2, as well as
antibodies targeting co-inhibitory molecules, like
PDCD1, CD274, and CTLA417,155
(table 3).156,157
Notably,
similar strategies have been suggested to remedy
Relevance in sepsis Relevance in HIV
Interleukin 7 Prevented apoptosis-inducedT-cell
depletion, and reversed sepsis-induced
depressionofT-cell cytokines in a murine
sepsis model
Improved lymphocyte function after ex-vivo
treatmentof cells from septic patients
Increase in functional naive and central
memoryCD4 andCD8T cells in clinicaltrials
Interleukin 15 Induces proliferation and activationof
T cells, natural killer cells and natural killer
T cells
Decreased apoptosis and improved survival
in a murine sepsis model
Theoretically,the same beneficial effects as in
sepsis might beobserved; however,delayed
viral suppression and failureto reconstitute
CD4T cells in SIV-infected macaquestreated
with interleukin 15discouraged further
research into interleukin 15 as an
immunomodulatorydrug
CSF2 Intargeted patient groups (thosewith low
HLA-DR expression inone study, and low
ex-vivotumour necrosis factor α producing
capacity)CSF2 increasedthe functionof
innate immune cells and improved clinical
outcomes
CSF2duringART interruptions blunted viral
rebound and preventedthedecreaseofCD4
cell counts156
PDCD1/CD274 Blockageof PDCD1or its ligand improved
survival in murine sepsis studies
Blockageof PDCD1 causedCD8T-cell and
B-cell activation, reduced viral load, and
improved survival in an SIV-macaque model.
PDCD1 blockade reduced hyperimmune
activation and microbialtranslocation in a
SIV-macaque model
CD274 blockade causedCD4T-cell restoration
in an ex-vivo studyusing PBMCs from patients
with HIV157
CTLA4 Anti-CTLA4treatment improved sepsis-
induced lymphocyte apoptosis and survival
from secondary fungal infections in a
murine sepsis model
Anti-CTLA4 treatment caused an increase in
CD4 and CD8 T cell responses and reduced
viral RNA in a SIV-macaque model
However, a second study with a similar
design reported no expansion of SIV specific
T cells and increased viral replication at
mucosal sites
Information in this table was derived from Hotchkiss et al and Hutchins et al17,155
for sepsis, andVanham andVan Gulck
for HIV,158
unless otherwise indicated in the table. ART=antiretroviral therapy. PBMC=peripheral blood mononuclear
cell. SIV=simian immunodeficiency virus.
Table 3: Parallels between the use of immunomodulatory agents in sepsis and HIV
Search strategy and selection criteria
We searched PubMed using the following search string:
(“HIV” [MeSH Terms] or “acquired immunodeficiency
syndrome” [MeSH Terms]) and (“immunity” [MeSH Terms]
or “monocytes” [MeSH Terms] or “macrophages” [MeSH
Terms] or “dendritic cell” [MeSH Terms] or “neutrophils”
[MeSH Terms] or “pattern recognition receptors” [MeSH
Terms] or “lymphocytes” [MeSH Terms] or “cytokines”
[MeSH Terms] or “complement system proteins” [MeSH
Terms] or “blood coagulation” [MeSH Terms] or
“disseminated intravascular coagulation” [MeSH Terms])
and (“bacteria” [MeSH Terms] or “sepsis” [MesH Terms] or
“bacteremia” [Mesh Terms)”. We also combined the MeSH
Terms for “salmonella” and “S pneumoniae” with the MeSH
Terms for “HIV” or “AIDS”. The search was limited to
English-language articles published between Jan 1, 1990
and June 1, 2014. We reviewed relevant articles identified in
this search, papers cited in these studies, and articles from
the authors’ personal files.

Review
HIV-induced immune suppression (table 3).158
Pro-
inflammatory and procoagulant pathways targeted by
novel sepsis therapies under clinical evaluation, such as
anti-HMGB1 strategies and soluble thrombo-
modulin,159,160
could be of interest for patients with HIV
and sepsis because HIV by itself already adversely
affects these mechanisms. Many pathogenic mecha-
nisms between sepsis and HIV overlap, so it is
conceivable that patients with HIV presenting with
sepsis form a group that will particularly benefit from
new drugs targeting septic immunosuppression. In
this light, the systematic exclusion of patients with HIV
from sepsis trials might need to be reconsidered.
Conclusion
In the era of effective cART, bacterial sepsis has evolved
as a major cause of mortality in patients with HIV. HIV
infection affects many components of the immune
response, which on the one hand renders the HIV-
infected host more susceptible to invasive infection, and
on the other hand might further exacerbate the
deregulated host response to sepsis. Specific research on
sepsis in patients with HIV is scarce and future studies
are needed to gain more insight into the particularities of
sepsis pathogenesis in these patients. Although cART
greatly improves patients’ immune function, as shown
by the strong reduction in opportunistic infections,
patients continue to have an increased risk of developing
invasive bacterial infection, suggesting the current and
future relevance of this under-researched area.
Declaration of interests
We declare no competing interests.
Contributors
MAH conceived the idea, searched the scientific literature, interpreted
the data, wrote the manuscript and created the figures. MPG and
TvdP. interpreted the data and wrote the manuscript.
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