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The eff ect of HIV infection on the host response to bacterial sepsisMichaëla 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 aff ects sepsis pathogenesis caused by pre-existing activation and exhaustion of the immune system. We review the eff ect of HIV on diff erent 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 benefi cial to patients with HIV co-infection because many pathogenic mechanisms in HIV and sepsis overlap.

IntroductionPeople 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 eff ective 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 proinfl ammatory and anti-infl ammatory eff ects, which result in organ failure.16,17 Likewise, HIV infection is characterised by a combination of immune suppression and chronic infl ammation, which results in exhaustion of the immune system.18 In this Review we describe how diff erent components of the immune response might be aff ected 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 defencesOverviewA sepsis event typically starts with a pathogen invading a normally sterile site. The fi rst line of defence consists of epithelial cells of the skin, gut, and lungs. After

breaching the epithelial barrier, pathogens are fi rst detected by innate immune cells, including monocytes, macro phages, 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 identifi ed: 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 com partments (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 amplifi er of host RNA-triggered infl ammation 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 infl ammation; hence TLR signalling is normally tightly regulated.

Innate immune cells have several specifi c functions in antibacterial immunity. Monocytes and macro phages have a crucial role in maintaining homoeostasis by phagocytosis of apoptotic cells and micro organisms.19 As the main producers of pro infl ammatory 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 OnlineOctober 20, 2014http://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, Prof T van der Poll MD); and Division of Infectious Diseases, Centre of Tropical 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, Netherlandsm.a.huson@amc.uva.nl

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antibacterial immune responses through the ability to directly lyse infected cells, provide early sources of proinfl ammatory cytokines, pre dominantly inter-feron-γ, induce dendritic cell maturation, and amplify the proinfl ammatory eff ects 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 proin fl ammatory cytokine release.27 Recruited neutrophils form an additional important fi rst 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 extra cellular 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 proinfl ammatory cytokines early in sepsis pathogenesis.29 The most extensively studied proinfl ammatory 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 infl ammatory 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 Proinfl ammatory 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 hyperinfl ammation 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 aff ects the fi rst 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 receptorsHIV 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 eff ect of diff erential 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 lipo poly saccharide, a

Study location and timeframe

Primary inclusion criteria

Patients infected with HIV(% of patients tested)

CA bacterial BSI in patients with HIV (%)

Main isolates in patients with HIV (%)

Mortality in patients with HIV with CA bacterial BSI

Archibald, 19985

Urban Tanzania, 1995

Febrile (≥37·5°C) admission

282 (55%) 51 (18%) NTS (45%), Escherichia coli (14%), Streptococcus pneumoniae (12%)

Not reported

Archibald, 20006

Urban Malawi, 1997

Febrile (≥37·5°C) admissions

173 (74%) 37 (21%) S pneumoniae (57%), NTS (30%)

Not reported

Arthur, 20017

Urban Kenya, 1988–97

Hospital admission

436 (32%) 87 (20%) NTS (46%), S pneumoniae (33%), E coli (6%)

39%

Bell, 20018 Urban Malawi, 1998

Febrile (37·5°C) admissions

173 (73%) 36 (21%) NTS (62%), E coli (7%), Salmonella Typhi (7%)

Not reported

Crump, 20119

Rural Tanzania, 2007–08

Febrile (≥38°C) admissions

161 (40%) 26 (16%) S pneumoniae (54%), E coli (12%), NTS (8%), S Typhi (8%)

Not reported

Grant, 199710

Ivory coast, 1995

Admission to the infectious disease unit

198 (79%) 39 (20%) NTS (59%), E coli (15%), S pneumoniae (10%)

46%

Mayanja, 201011

Rural Uganda, 1996–2007

Fever (≥38°C) with no detectable malaria parasites

488 (64%) 152 (31%) S pneumoniae (43%), NTS (26%), E coli (6%)

Not reported

Meremo, 201212

Urban Tanzania, 2011

Hospital admission with fever (>37·5°C)

156 (45%) 16 (10%) NTS (75%) 35%

Nadjm, 201213

Rural Tanzania, 2007

Fever and one severity criterion

69 (35%) 12 (17%) NTS (25%), S pneumoniae (25%), Streptococcus pyogenes (17%)

25%

Peters, 200414

Urban Malawi, 2000

Admission with fever (≥37·4°C) or history of fever in the past 4 days

291 (83%) 66 (23%) NTS (67%), S pneumoniae (20%), E coli (6%)

Not reported

Ssali, 199815

Uganda, 1997 Admission with fever (>38°C)

222 (76%) 33 (15%) Salmonella spp (39%), S pneumoniae (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

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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 diff er according to cell type. Increased expression of TLRs on cytokine-producing cells might contribute to aberrant infl ammation in the disturbed homoeostasis in sepsis, although this possibility has not yet been addressed in in-vivo studies.

Monocytes and macrophagesThe eff ect 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, proinfl ammatory 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 infl amed tissue in chronic infl ammatory diseases such as rheumatoid arthritis, was identifi ed as the predominant cell type responsible for TNFα overproduction46 (table 2).47–67

Several studies also examined the eff ect 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, and CSF248,49

Cytokine levels normalised after treatment with cART47,48

Two studies50,51 examined cytokine levels in sepsis patients, but recorded no diff erences, except higher interleukin 10 concentrations in HIV co-infected patients in one of these studies50

Decreased CSF2 levels were seen in patients with HIV with advanced disease

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 cells were identifi ed as the main cell type responsible for TNFα overproduction46

Increased levels of M-DC8 monocytes were recorded in viraemic patients with HIV, but not in virally suppressed patients on cART46

Alveolar macrophages

Ex-vivo stimulation

↓ TNFα, interleukin 8, interleukin 1253–56 Reports confl ict on this subject; other studies noted increased interleukin 8, 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-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 10 and interleukin 106060

Most reports describe decreased cytokine production after stimulation, but normal,62 or even increased cytokine responses to stimulation were also reported63

Natural killer cells

Ex-vivo stimulation

↓ Interferon γ64 The eff ect was observed in both cART-treated and untreated patients64

Natural killer T cells

Ex-vivo stimulation

↓ Interferon γ and interleukin 465 Stimulations were done with marine sponge-derived α-galactosylceramide (αGalCer) as a ligand;65 similar studies using bacterial ligands as a stimulus were not availableCytokine 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 Th17 cells

Ex-vivo stimulation

↓ Interleukin 22, TNFα, and interferon γ67

↑ Interleukin 1067

Restoration of cytokine responses was seen after prolonged treatment with 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 specifi ed.

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

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macrophage phagocytosis of S pneumoniae was previously reported,37 a study68 noted impaired phago-cytosis in HIV-infected small alveolar macro phages, 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 (fi gure 1). Another study56 noted increased production of both proinfl ammatory (interleukin 8 and 12) and anti-infl ammatory (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 pneu monia,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 proinfl ammatory cytokine release, especially in alveolar macrophages. These defects might contribute to increased susceptibility to bacterial infection and deregulated infl ammation.

Dendritic cellsIn patients with HIV, around 10–15% of dendritic cells are infected,57 but HIV also aff ects 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↓CD4T 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 pneumoniaeIn 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. Ineff ective 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 fl uid are reduced in patients with HIV, thereby hindering an eff ective proinfl ammatory response. Alveolar macrophages from patients with HIV produce lower concentrations of interleukin 8 in response to S pneumoniae, resulting in less eff ective 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 infl ux. The combination of impairments in antipneumococcal defence enables the invasion of S pneumoniae into the bloodstream. TNFα=tumour necrosis factor α.

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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 eff ect 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 cellsReduced 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 specifi cally address antibacterial immune responses by NK cells from patients with HIV, many studies report on HIV-induced changes that prevent an eff ective anti-HIV NK cell response, which might also result in impaired anti bacterial 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 eff ects were reversed in virally suppressed patients on cART.85,86 No studies on NK T-cell antibacterial defence in HIV-infected hosts were identifi ed, but selective NK T-cell depletion might hinder the proinfl ammatory 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.

NeutrophilsIn patients with HIV infection, neutrophils might not be able to function eff ectively 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 proinfl ammatory 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

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could impair eff ective 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 DAMPsAbundant evidence suggests a change in cytokine profi les 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 infl am matory parameters in patients with sepsis admitted to the ICU with or without HIV co-infection. A wide range of cytokines were measured, but no signifi cant diff erences 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 diff ered 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 proinfl ammatory cytokines interleukin 12, and CSF2, were decreased.49,48 Studies on the eff ect of cART noted normalisation of most cytokine perturbations.47,48

Raised concentrations of circulating infl ammatory markers might in fact be associated with the development of infection; a correlation was identifi ed 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 con centrations might relate to the type of stimulus and stage of disease, with patients with AIDS showing the most profound defi ciency.102

There is abundant evidence for increased circulating concentrations of both proinfl ammatory and

anti-infl ammatory 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 diff erences in cytokine concentrations compared with HIV-negative patients with sepsis.

LymphocytesOverviewAntigen-presenting cells interact with lymphocytes to initiate the adaptive immune response. In response to the presentation of antigen, eff ector 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 proinfl ammatory response.104 Remaining lymphocytes also show signifi cant reductions in cytokine release on stimulation.105

T lymphocytesDuring 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 effi ciently 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-infl ammatory phenotype (table 2).67 Similarly, increased interleukin 10 production was identifi ed in peripheral blood CD4 T cells.66 Mucosal-associated invariant T cells (MAIT cells), a subset of innate-like, tissue-infi ltrating 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

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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 (fi gure 2).114 Additionally, interleukin-17-producing CD4 T cells were shown to be essential for recruitment of monocytes and macrophages to allow for eff ective 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 (fi gure 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 diff erentiated phenotype,119 and is unable to mount an eff ective 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-lymphocytesIn 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 hypergam maglo-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, CD21lowCD27− 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 (fi gure 1) and non-typhoidal salmonella (fi gure 2). Patients with HIV have reduced numbers of pneumococcal antigen-specifi c IgG antibody-secreting cells and lower concentrations of pneumococcal antibodies.124,132 Additionally, IgA in the epithelial lining fl uid of the lung showed impaired antipneumococcal activity.133 Although some studies reported normal,134 or even

Th17

↓Interleukin 17

Intestinal lumen

Laminapropria

Bloodstream

Interleukin 17

NTS in the gutof a host withoutHIV infection

NTS in the gut of an HIV-infectedhost

Th17 depletionand reduced interleukin 17 compromise gut barrier function

Inhibitory antibodies bindto LPS, whichprevents bacterial killing

Binding of IgG to outermembraneproteinsenables bacterial lysisand killing

C1q

LPS

MAC

Figure 2: HIV-induced changes in host defence against non-typhoidal salmonella (NTS) infection from the gutNormally, interleukin-17-producing Th17 cells eff ectively 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 eff ectively 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 eff ect 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.

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increased concentrations of IgG anti-pneumococcal-specifi c 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 eff ect 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 (fi 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 systemPatients 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 intra vascular 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 fi 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 identifi ed (fi 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 fi 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 protein S,138,143 and fi brinolysis might be impaired as a con sequence of increased SERPINE concentrations in patients with HIV.139,143 Last, ample evidence shows endothelial activation and dysfunction in patients with HIV. Raised con centrations of VWF, soluble ICAM1, and soluble VCAM1 have been reported in several studies.138,143,144 Additionally, endothelial function, assessed by measuring fl 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 signifi cantly higher con centrations 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 eff ect of cART are inconsistent, with some recording complete normalisation144 and others reporting partial improve ment,136,149 as well as studies describing a detrimental eff ect of cART, especially regimens containing protease inhibitors.137,150

At present, no studies on the eff ect 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 systemThe complement system is an important part of the fi rst-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 factorCoagulation 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

Figure 3: HIV-induced changes in the coagulation system and endothelium resemble sepsis-induced coagulopathyExpression 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 fi brinogen to fi brin. Increased concentrations of fi brinogen and D-dimer, a fi 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, fi 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.

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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 proinfl ammatory 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-specifi c 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 proinfl ammatory and anti-infl ammatory mechanisms. However, at present, studies investigating the eff ect of HIV infection on complement activation in sepsis have not been reported.

Future perspectivesThe 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 infl ammatory response generally held responsible for sepsis mortality.19,21 In more recent years, however, attention has shifted to fi 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

Relevance in sepsis Relevance in HIV

Interleukin 7 Prevented apoptosis-induced T-cell depletion, and reversed sepsis-induced depression of T-cell cytokines in a murine sepsis modelImproved lymphocyte function after ex-vivo treatment of cells from septic patients

Increase in functional naive and central memory CD4 and CD8 T cells in clinical trials

Interleukin 15 Induces proliferation and activation of T cells, natural killer cells and natural killer T cellsDecreased apoptosis and improved survival in a murine sepsis model

Theoretically, the same benefi cial eff ects as in sepsis might be observed; however, delayed viral suppression and failure to reconstitute CD4 T cells in SIV-infected macaques treated with interleukin 15 discouraged further research into interleukin 15 as an immunomodulatory drug

CSF2 In targeted patient groups (those with low HLA-DR expression in one study, and low ex-vivo tumour necrosis factor α producing capacity) CSF2 increased the function of innate immune cells and improved clinical outcomes

CSF2 during ART interruptions blunted viral rebound and prevented the decrease of CD4 cell counts156

PDCD1/CD274 Blockage of PDCD1 or its ligand improved survival in murine sepsis studies

Blockage of PDCD1 caused CD8 T-cell and 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 modelCD274 blockade caused CD4 T-cell restoration in an ex-vivo study using PBMCs from patients with HIV157

CTLA4 Anti-CTLA4 treatment 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 modelHowever, a second study with a similar design reported no expansion of SIV specifi c 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 immunodefi ciency 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 immunodefi ciency 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 identifi ed in this search, papers cited in these studies, and articles from the authors’ personal fi les.

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HIV-induced immune sup pression (table 3).158 Pro-infl ammatory 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 aff ects 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 benefi t from new drugs targeting septic immuno suppression. In this light, the systematic exclusion of patients with HIV from sepsis trials might need to be reconsidered.

ConclusionIn the era of eff ective cART, bacterial sepsis has evolved as a major cause of mortality in patients with HIV. HIV infection aff ects 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. Specifi c 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 interestsWe declare no competing interests.

ContributorsMAH conceived the idea, searched the scientifi c literature, interpreted the data, wrote the manuscript and created the fi gures. MPG and TvdP. interpreted the data and wrote the manuscript.

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