Review

The eect of HIV infection on the host response to

bacterial sepsis
Michala 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 Lancet Infect Dis 2015;
susceptibility to invasive infections and aects sepsis pathogenesis caused by pre-existing activation and exhaustion 15: 95108
of the immune system. We review the eect of HIV on dierent components of immune responses implicated in Published Online
October 20, 2014
bacterial sepsis, and possible mechanisms underlying the increased risk of invasive bacterial infections. We focus
http://dx.doi.org/10.1016/
on pattern recognition receptors and innate cellular responses, cytokines, lymphocytes, coagulation, and the S1473-3099(14)70917-X
complement system. A combination of factors causes increased susceptibility to infection and can contribute to a Division of Infectious Diseases,
disturbed immune response during a septic event in patients with HIV. HIV-induced perturbations of the immune Centre of Experimental and
system depend on stage of infection and are only in part restored by combination antiretroviral therapy. Immuno- Molecular Medicine
modulatory treatments currently under development for sepsis might be particularly benecial to patients with (M A M Huson MD,
Prof T van der Poll MD); and
HIV co-infection because many pathogenic mechanisms in HIV and sepsis overlap. Division of Infectious Diseases,
Centre of Tropical Medicine and
Introduction breaching the epithelial barrier, pathogens are rst Travel Medicine, Academic
Medical Centre, University of
People infected with HIV are at increased risk of detected by innate immune cells, including monocytes,
Amsterdam, Amsterdam,
developing other infections. Reports from developed macrophages, dendritic cells, and neutrophils.19 These Netherlands
countries show that, with the introduction of cells express pattern recognition receptors (PRRs) on (Prof M P Grobusch MD)
combination antiretroviral therapy (cART), the incidence their surface and in the cytosol to enable recognition of Correspondence to:
of opportunistic infections such as Pneumocystis jirovecii conserved motifs expressed by pathogens.20,21 Four Dr Michala A M Huson,
pneumonia has decreased substantially, and sepsis is classes of PRRs have been identied: toll-like receptors Academic Medical Centre,
University of Amsterdam,
now the principal cause of intensive care unit (ICU) (TLRs), C-type lectin receptors (CLRs), nucleotide- Amsterdam 1105 AZ,
admission and death in patients with HIV who are binding oligomerisation domain leucine-rich-repeat Netherlands
admitted to hospital.1 Worldwide, patients with HIV are containing receptors (NOD-LRRs), and retinoic acid- m.a.huson@amc.uva.nl
at increased risk of developing bacterial bloodstream inducible geneI protein helicase receptors (RLRs).20 In
infections, particularly with non-typhoidal salmonella the context of sepsis pathogenesis, TLRs have been
(NTS) and Streptococcus pneumoniae,2,3 even in those studied the most extensively. They are expressed on the
using eective cART.4 In developing regions with high cell surface (TLRs 1, 2, 4, 5, and 6) to enable recognition
rates of HIV infection, the scale of the problem is of bacterial outer membrane components, and in
immense. In African hospitals, 3183% of patients intracellular compartments (TLRs 3, 7, 8, and 9) for
presenting with fever are infected with HIV, and 1032% detection of nucleic acids derived from intracellular
of these patients have bacterial bloodstream infections, pathogens, mainly viruses.20 For bacterial recognition,
with mortality rates of 2546% (table 1).5-15 However, little TLRs 2, 4, 5, and 9 are the most important. Additionally,
is known about the particularities of the host response TLR7 can sense bacterial RNA released within
during bacterial sepsis in patients with HIV. The phagosomal vacuoles,22 and TLR3 can function as an
immune response during sepsis is thought to be an amplier of host RNA-triggered inammation during
imbalance between proinammatory and anti- sepsis.23 Ligand recognition by TLRs triggers a
inammatory eects, which result in organ failure.16,17 signalling cascade, which results in the production of
Likewise, HIV infection is characterised by a cytokines.20 Although essential for pathogen recognition
combination of immune suppression and chronic and the innate immune response, uncontrolled
inammation, which results in exhaustion of the stimulation causes excessive inammation; hence TLR
immune system.18 In this Review we describe how signalling is normally tightly regulated.
dierent components of the immune response might be Innate immune cells have several specic functions in
aected by HIV during bacterial sepsis, and possible antibacterial immunity. Monocytes and macrophages
mechanisms for the increased risk of invasive bacterial have a crucial role in maintaining homoeostasis by
infections. We also discuss parallels in immuno- phagocytosis of apoptotic cells and microorganisms.19
modulatory therapies proposed for sepsis and HIV, As the main producers of proinammatory cytokines,
which represent an appealing area for future research. they are also thought to be key in sepsis pathogenesis.19
Dendritic cells are the main antigen-presenting cells;
First line defences maturation is induced after ingestion of antigen,
Overview followed by migration to lymphoid tissue. Mature
A sepsis event typically starts with a pathogen invading dendritic cells express co-stimulatory molecules on
a normally sterile site. The rst line of defence consists their surface, which synergise with antigen to activate
of epithelial cells of the skin, gut, and lungs. After T cells.24 Natural killer (NK) cells are implicated in

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 Review

Likewise, natural killer T cells (NK T cells), a subset that

Study location Primary Patients CA Main isolates in Mortality in
and timeframe inclusion infected with bacterial patients with patients shares cell-surface proteins with conventional T cells
criteria HIV BSI in HIV (%) with HIV and NK cells, have been implicated in sepsis
(% of patients patients with CA pathogenesis because of their strong proinammatory
tested) with HIV bacterial BSI
(%)
cytokine release.27 Recruited neutrophils form an
additional important rst line of defence against
Archibald, Urban Tanzania, Febrile 282 (55%) 51 (18%) NTS (45%), Not reported
19985 1995 (375C) Escherichia coli
invading pathogens. They kill microbes through
admission (14%), phagocytosis, the release of lytic enzymes from their
Streptococcus granules, the production of reactive oxygen inter-
pneumoniae mediates, and the formation of neutrophil extracellular
(12%)
traps (NETs)lattices of chromatin decorated with anti-
Archibald, Urban Malawi, Febrile 173 (74%) 37 (21%) S pneumoniae Not reported
20006 1997 (375C) (57%), NTS microbial proteins with strong bactericidal capacity.28
admissions (30%) The innate immune system is thought to be mostly
Arthur, Urban Kenya, Hospital 436 (32%) 87 (20%) NTS (46%), 39% responsible for the excessive release of proinammatory
20017 198897 admission S pneumoniae cytokines early in sepsis pathogenesis.29 The most
(33%), E coli (6%)
extensively studied proinammatory cytokines in
Bell, 20018 Urban Malawi, Febrile 173 (73%) 36 (21%) NTS (62%), E coli Not reported
sepsis are tumour necrosis factor (TNF) and
1998 (375C) (7%), Salmonella
admissions Typhi (7%) interleukin 1, both of which are capable of activating
Crump, Rural Tanzania, Febrile 161 (40%) 26 (16%) S pneumoniae Not reported target cells and induce the production of more
20119 200708 (38C) (54%), E coli inammatory mediators.29 Additionally, host cells
admissions (12%), NTS (8%), release damage-associated molecular patterns (DAMPs)
S Typhi (8%)
in response to pathogens or injury, which are recognised
Grant, Ivory coast, Admission 198 (79%) 39 (20%) NTS (59%), E coli 46%
199710 1995 to the (15%),
by PRRs, thereby enhancing immune activation. The
infectious S pneumoniae most investigated DAMP is HMGB1, which signals via
disease unit (10%) TLR2, TLR4, and TLR9 to induce cytokine release,
Mayanja, Rural Uganda, Fever 488 (64%) 152 (31%) S pneumoniae Not reported activation of coagulation, and neutrophil recruitment.30
201011 19962007 (38C) with (43%), NTS Proinammatory cytokines and DAMPs seem to have a
no (26%), E coli (6%)
detectable double role in sepsis pathogenesis; they are essential
malaria for an adequate innate defence during early stage
parasites infection, but also contribute to hyperinammation
Meremo, Urban Tanzania, Hospital 156 (45%) 16 (10%) NTS (75%) 35% during late phase uncontrolled infection.20,21 In patients
201212 2011 admission
with fever
with severe sepsis and in murine sepsis models, high
(>375C) concentrations of interleukins 1, 6, 8, and 17, CCL2,
Nadjm, Rural Tanzania, Fever and 69 (35%) 12 (17%) NTS (25%), 25% CSF3, and HMGB1 are associated with mortality.29
201213 2007 one severity S pneumoniae HIV aects the rst lines of defence in several ways.
criterion (25%), First, defects of epithelial barriers are common and
Streptococcus
pyogenes (17%) have been particularly well described for the gut. In the
Peters, Urban Malawi, Admission 291 (83%) 66 (23%) NTS (67%), Not reported gut, HIV causes barrier defects during acute infection,
200414 2000 with fever S pneumoniae which are maintained during chronic infection, thereby
(374C) or (20%), E coli (6%) enabling invasive infections by intestinal pathogens
history of
fever in the
such as non-typhoidal salmonella.31 Furthermore,
past 4 days microbial products that translocate into the circulation
Ssali, Uganda, 1997 Admission 222 (76%) 33 (15%) Salmonella spp Not reported fuel chronic immune activation and exhaustion.32
199815 with fever (39%),
(>38C) S pneumoniae Toll-like receptors
(33%)
HIV infection and AIDS are associated with increased
Data was derived from prospective observational studies, which were previously described by Huson and colleagues.3 TLR2, TLR3, TLR4, TLR7, and TLR9 expression on
CA=community acquired. BSI=bloodstream infection. NTS=non-typhoidal salmonella. various cells, including T lymphocytes, monocytes,
Table 1: Burden of community-acquired bacterial bloodstream infections in patients with HIV in African macrophages, and dendritic cells,3338 although one study34
countries where HIV is highly prevalent reported lower peripheral blood mononuclear cell
(PBMC) RNA expression levels of TLR3, TLR4, and TLR9
in patients with chronic HIV unresponsive to cART.
antibacterial immune responses through the ability to Reports on the functional eect of dierential TLR
directly lyse infected cells, provide early sources of expression are inconsistent. Ex-vivo studies with PBMCs
proinammatory cytokines, predominantly inter- from patients with HIV noted a correlation between
feron-, induce dendritic cell maturation, and amplify increased expression of TLRs and increased TNF
the proinammatory eects of myeloid cells.25,26 production after stimulation with lipopolysaccharide, a

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 Review

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 dier
according to cell type. Increased expression of TLRs on
cytokine-producing cells might contribute to aberrant
inammation in the disturbed homoeostasis in sepsis,
although this possibility has not yet been addressed in
in-vivo studies.
Monocytes and macrophages
The eect 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). See Online for 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, proinammatory 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 inamed tissue in chronic
inammatory diseases such as rheumatoid arthritis, was
identied as the predominant cell type responsible for
TNF overproduction46 (table 2).4767
Several studies also examined the eect of HIV on the
alveolar compartment. Although normal alveolar

Study condition* HIV-induced changes Comments

Whole blood In vivo Interleukin 6, interleukin 10, TNF, Cytokine levels normalised after treatment with cART47,48
interleukin 1, interleukin 1, interleukin 8, Two studies50,51 examined cytokine levels in sepsis patients, but recorded no
CCL2, interleukin 1R1, and interferon 47,48 dierences, except higher interleukin 10 concentrations in HIV co-infected
interleukin 12, and CSF248,49 patients in one of these studies50
Decreased CSF2 levels were seen in patients with HIV with advanced disease
Peripheral blood Ex-vivo and in- TNF 38,46,52
mononuclear vitro stimulation
cells
Monocytes Ex-vivo Interleukin 6, interleukin 1, TNF44
stimulation
M-DC8 Ex-vivo TNF46 These cells were identied as the main cell type responsible for TNF
monocytes stimulation overproduction46
Increased levels of M-DC8 monocytes were recorded in viraemic patients
with HIV, but not in virally suppressed patients on cART46
Alveolar Ex-vivo TNF, interleukin 8, interleukin 125356 Reports conict on this subject; other studies noted increased interleukin 8,
macrophages stimulation 12 and 10 in alveolar macrophages of patients with HIV56
Impaired interleukin 12 production was only reported in patients with
advanced disease56
Dendritic cells In-vitro and ex- Interleukin 12,5759 interleukin 6,58 Most reports describe decreased cytokine production after stimulation, but
vivo stimulation interferon ,58,60 interferon ,59,61 normal,62 or even increased cytokine responses to stimulation were also
interleukin 2,61 and interleukin 1060 reported63
Natural killer Ex-vivo Interferon 64 The eect was observed in both cART-treated and untreated patients64
cells stimulation
Natural killer Ex-vivo Interferon and interleukin 465 Stimulations were done with marine sponge-derived -galactosylceramide
T cells stimulation (GalCer) as a ligand;65 similar studies using bacterial ligands as a stimulus
were not available
Cytokine secretion was restored by cART65
CD4 T cells In-vivo Interleukin 1066 Interleukin 10 production was increased in chronic progressors and recently
infected individuals, but not in non-progressors with HIV66
Gut mucosa Ex-vivo Interleukin 22, TNF, and interferon 67 Restoration of cytokine responses was seen after prolonged treatment with
Th17 cells stimulation Interleukin 1067 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 specied.

Table 2: Eect of HIV infection on the cytokine milieu by cell type

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 Review

S pneumoniae
Nasopharyngeal cavity

Nasopharynx interstitium
CD4
T cells Interleukin 17 Macrophage recruitment

Opsonic capacity of IgA ( ) and IgG ( )

Alveolar space

Alveolar interstitium

TNF
Neutrophil recruitment
Interleukin 8

Macrophage phagocytosis

Bloodstream

Bloodstream invasion of S pneumoniae

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. Ineective opsonisation also
impairs phagocytosis by alveolar macrophages. Furthermore, alveolar macrophages from HIV-positive patients showed decreased TNF production in response
to TLR2 and TLR4 ligands, and concentrations of TNF in bronchoalveolar lavage uid are reduced in patients with HIV, thereby hindering an eective
proinammatory response. Alveolar macrophages from patients with HIV produce lower concentrations of interleukin 8 in response to S pneumoniae, resulting
in less eective 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 inux. The combination of impairments in antipneumococcal defence enables
the invasion of S pneumoniae into the bloodstream. TNF=tumour necrosis factor .

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 TNF, in response to
TLR2 and TLR4 ligands, was impaired in alveolar
macrophages from patients with HIV (table 2).5355
Considering the crucial role of TNF 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 (gure 1). Another study56
noted increased production of both proinammatory
(interleukin 8 and 12) and anti-inammatory
(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 proinammatory cytokine
release, especially in alveolar macrophages. These
defects might contribute to increased susceptibility to
bacterial infection and deregulated inammation.
Dendritic cells
In patients with HIV, around 1015% of dendritic cells
are infected,57 but HIV also aects 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

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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 eect 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 12,5759 interleukin 6,58 interferon
,58,59 interferon ,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--producing NK
cells (table 2).64 Although this study is the only one to
specically address antibacterial immune responses by
NK cells from patients with HIV, many studies report
on HIV-induced changes that prevent an eective 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
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Review
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 eects were reversed in virally
suppressed patients on cART.85,86 No studies on NK
T-cell antibacterial defence in HIV-infected hosts were
identied, but selective NK T-cell depletion might
hinder the proinammatory 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 eectively 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.40,9496 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
proinammatory 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
99
 Review
could impair eective 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
proles 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
inammatory parameters in patients with sepsis
admitted to the ICU with or without HIV co-infection.
A wide range of cytokines were measured, but no
signicant dierences 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
diered 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, TNF, interleukin 1A,
interleukin 1, interleukin 8, CCL2, interleukin 1
receptor antagonist, and, in acute HIV infection,
interferon . Concentrations of HMGB1 were also
increased in patients with HIV.100 However, circulating
concentrations of the proinammatory cytokines
interleukin 12, and CSF2, were decreased.49,48 Studies on
the eect of cART noted normalisation of most cytokine
perturbations.47,48
Raised concentrations of circulating inammatory
markers might in fact be associated with the
development of infection; a correlation was identied
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 TNF 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 deciency.102
There is abundant evidence for increased circulating
concentrations of both proinammatory and
100
anti-inammatory 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 dierences 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, eector CD4 T cells secrete
cytokines, such as interferon , 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 proinammatory
response.104 Remaining lymphocytes also show
signicant 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 eciently
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:TNF ratio, suggestive of
an anti-inammatory phenotype (table 2).67 Similarly,
increased interleukin 10 production was identied in
peripheral blood CD4 T cells.66 Mucosal-associated
invariant T cells (MAIT cells), a subset of innate-like,
tissue-inltrating lymphocytes that produce
interleukin17, interleukin 22, interferon , and TNF,
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
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 Review

gut were relatively preserved in these studies,110,111 a NTS in the gut NTS in the
third study reported MAIT cell depletion in the colon of of a host without gut of an
patients with HIV.112 Since MAIT cells are known to be HIV infection HIV-infected
host
activated by a wide range of bacteria and fungi,113 their Intestinal lumen
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 Lamina Interleukin 17 Th17 depletion
increased risk of patients with HIV developing non- propria and reduced
interleukin 17
typhoidal salmonella bacteraemia, because interleukin compromise
17 is known to have an important role in host defence Th17
gut barrier
Interleukin 17 function
against dissemination of enteric pathogens (gure 2).114
Additionally, interleukin-17-producing CD4 T cells were
shown to be essential for recruitment of monocytes and Bloodstream
macrophages to allow for eective pneumococcal
clearance from the nasopharynx,115 suggesting that CD4
cell depletion has a role in the vulnerability of patients
C1q
with HIV to the invasive pneumococcal infections
(gure 1). Binding of
IgG to outer
Although CD4 T-cell counts decrease, CD8 T-cell membrane
MAC
Inhibitory
numbers expand during HIV infection.116 Nonetheless, proteins
LPS
antibodies bind
enables to LPS, which
both T-cell compartments display a phenotype of bacterial lysis prevents
immune activation and exhaustion, as suggested by and killing bacterial killing
heightened expression of the activation markers HLA-
DR and CD38, and of the inhibitory receptors PDCD1 Figure 2: HIV-induced changes in host defence against non-typhoidal salmonella (NTS) infection from the gut
Normally, interleukin-17-producing Th17 cells eectively prevent invasion of NTS from the gut (left side), but
and CTLA4 in untreated patients with HIV.117,118
HIV infection results in Th17 cell depletion and reduced interleukin 17 concentrations, thereby compromising
Furthermore, the CD8 T-cell compartment has been the gut barrier function against NTS (right side). If NTS bacteria manage to reach the bloodstream in a host
shown to arrest at a late dierentiated phenotype,119 and without HIV infection, they are eectively opsonised by IgG antibodies that bind to the outer membrane
is unable to mount an eective cytolytic response.120,121 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
Both reduction in CD4 T-cell numbers, and functional
opsonised by antibodies that have an inhibitory eect on bacterial killing. They do not bind to the outer
impairments of CD4 T cells and CD8 T cells might membrane protein of the NTS, but to its LPS, which does not enable lysis and killing, and allows for survival of
contribute to increased susceptibility of patients with NTS in the bloodstream (right side). NTS=non-typhoid salmonella. MAC=membrane attack complex.
HIV to develop invasive bacterial infections and sepsis. LPS=lipopolysaccharide.
Most of these defects can be restored by cART,106 but
impaired restoration of the CD4 T-cell proliferation are severely depleted, whereas transitional B cells are
response has been described in patients with HIV with expanded.123 An aberrant B-cell population,
lower nadir CD4 T-cell counts before therapy,122 thus CD21lowCD27 B cells, normally present in very low
providing one possible explanation for higher rates of numbers in peripheral blood, was reported to rise in
bacteraemia in cART-treated patients compared with the blood of viraemic patients with HIV proportional to
HIV-negative people. viral load,128 which showed features of immune
activation and cellular exhaustion.129 Although changes
B-lymphocytes in most B-cell subtypes are restored by cART, resting
In patients with HIV, several defects in B-cell function memory B cells usually remain depleted128 because they
have been detected, which could have a role in increased can only be preserved when cART is started early in
susceptibility to infections, especially in patients with infection.130 Additionally, IgG concentrations were
non-typhoidal salmonella and S pneumoniae (appendix). shown to remain raised despite long-term cART in 45%
Functional disturbances include hypergammaglo- of patients, indicating continuous B-cell activation.131
bulinaemia, polyclonal activation and exhaustion, B-cell dysfunction probably has an important role in
impaired class-switch recombination, dysfunctional the increased risk of patients with HIV developing
interaction between T cells and B cells, blunted invasive infections with S pneumoniae (gure 1) and
proliferation response to both T-cell-dependent and non-typhoidal salmonella (gure 2). Patients with HIV
T-cell-independent antigens, poor immune responses have reduced numbers of pneumococcal antigen-
against vaccination antigens, short duration of antibody specic IgG antibody-secreting cells and lower
response induced by pneumococcal vaccination, and concentrations of pneumococcal antibodies.124,132
increased apoptosis.123127 Additionally, IgA in the epithelial lining uid of the
Additionally, patients with HIV show changes in the lung showed impaired antipneumococcal activity.133
distribution of B-cell subsets. Resting memory B cells Although some studies reported normal,134 or even

www.thelancet.com/infection Vol 15 January 2015 101

 Review
increased concentrations of IgG anti-pneumococcal-
specic 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 eect 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 (gure 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
Increased coagulation Impaired anticoagulation and brinolysis
Protein C
Protein S
Tissue factor
Coagulation cascade Activated protein C
Fibrinogen Fibrin SERPINE
D-dimer Thrombus formation Fibrinolysis
sICAM1
sVCAM1 VWF
ANGPT2
Endothelial activation and damage
Figure 3: HIV-induced changes in the coagulation system and endothelium resemble sepsis-induced coagulopathy
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 brinogen to brin.
Increased concentrations of brinogen and D-dimer, a brin 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, brinolysis 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.
102
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
brinolysis 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 identied (gure 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 brinogen,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 proteinS,138,143 and brinolysis 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 ow-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 signicantly
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 eect of cART are inconsistent, with some
recording complete normalisation144 and others
reporting partial improvement,136,149 as well as studies
describing a detrimental eect of cART, especially
regimens containing protease inhibitors.137,150
At present, no studies on the eect 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
rst-line host defence against bacteria, by opsonisation,
lysis of pathogens and infected cells, and production of
chemoattractants. Clinical and experimental sepsis are
www.thelancet.com/infection Vol 15 January 2015

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
proinammatory 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-specic
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
proinammatory and anti-inammatory mechanisms.
However, at present, studies investigating the eect 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 inammatory response generally held
responsible for sepsis mortality.19,21 In more recent
years, however, attention has shifted to ndings 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
www.thelancet.com/infection Vol 15 January 2015
Review
Relevance in sepsis Relevance in HIV
Interleukin 7 Prevented apoptosis-induced T-cell Increase in functional naive and central
depletion, and reversed sepsis-induced memory CD4 and CD8 T cells in clinical trials
depression of T-cell cytokines in a murine
sepsis model
Improved lymphocyte function after ex-vivo
treatment of cells from septic patients
Interleukin 15 Induces proliferation and activation of Theoretically, the same benecial eects as in
T cells, natural killer cells and natural killer sepsis might be observed; however, delayed
T cells viral suppression and failure to reconstitute
Decreased apoptosis and improved survival CD4 T cells in SIV-infected macaques treated
in a murine sepsis model with interleukin 15 discouraged further
research into interleukin 15 as an
immunomodulatory drug
CSF2 In targeted patient groups (those with low CSF2 during ART interruptions blunted viral
HLA-DR expression in one study, and low rebound and prevented the decrease of CD4
ex-vivo tumour necrosis factor producing cell counts156
capacity) CSF2 increased the function of
innate immune cells and improved clinical
outcomes
PDCD1/CD274 Blockage of PDCD1 or its ligand improved Blockage of PDCD1 caused CD8 T-cell and
survival in murine sepsis studies B-cell activation, reduced viral load, and
improved survival in an SIV-macaque model.
PDCD1 blockade reduced hyperimmune
activation and microbial translocation in a
SIV-macaque model
CD274 blockade caused CD4 T-cell restoration
in an ex-vivo study using PBMCs from patients
with HIV157
CTLA4 Anti-CTLA4 treatment improved sepsis- Anti-CTLA4 treatment caused an increase in
induced lymphocyte apoptosis and survival CD4 and CD8 T cell responses and reduced
from secondary fungal infections in a viral RNA in a SIV-macaque model
murine sepsis model However, a second study with a similar
design reported no expansion of SIV specic
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, and Vanham and Van Gulck
for HIV,158 unless otherwise indicated in the table. ART=antiretroviral therapy. PBMC=peripheral blood mononuclear
cell. SIV=simian immunodeciency 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 immunodeciency
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 identied in
this search, papers cited in these studies, and articles from
the authors personal les.
103
 Review
HIV-induced immune suppression (table 3).158 Pro-
inammatory 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
aects 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 benet 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 eective cART, bacterial sepsis has evolved
as a major cause of mortality in patients with HIV. HIV
infection aects 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. Specic 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 scientic literature, interpreted
the data, wrote the manuscript and created the gures. MPG and
TvdP. interpreted the data and wrote the manuscript.
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