Infection (2014) 42:951–959
DOI 10.1007/s15010-014-0666-5
REVIEW
Intestinal barrier dysfunction in HIV infection: pathophysiology,
clinical implications and potential therapies
S. F. Assimakopoulos • D. Dimitropoulou •
M. Marangos • C. A. Gogos
Received: 21 April 2014 / Accepted: 11 July 2014 / Published online: 29 July 2014
Ó Springer-Verlag Berlin Heidelberg 2014
Abstract
Introduction Current pathogenetic aspects on HIV
infection highlight the importance of a chronic immune
activation ultimately leading to T lymphocyte homeostasis
disruption and immune deregulation associated with dis-
ease manifestations and progression. It is widely accepted
that this continuous immune activation in HIV infection is
principally driven by the phenomenon of pathological
microbial translocation (MT).
Methods Review of the literature on the role of intestinal
barrier dysfunction in HIV infection, with emphasis on the
implicated pathophysiological mechanisms, clinical impli-
cations and potentially effective therapeutic interventions.
Findings MT in HIV infection is promoted by a multi-
factorial disruption of all major levels comprising the
intestinal barrier defense. Specifically, HIV infection dis-
rupts the integrity of the intestinal biological (quantitative
and qualitative alterations of gut microecology, overgrowth
of pathogenic bacteria), immune (depletion of CD4(?) T
cells, especially Th17 cells, increased CD4? FoxP3?
Tregs, decreased mucosal macrophages phagocytic capac-
ity, development of intestinal proinflammatory milieu) and
mechanical barrier (enterocytes’ apoptosis, disruption of
tight junctions). Intestinal barrier dysfunction allows the
passage of microbes and immunostimulatory bioproducts
from the gut lumen first in the lamina propria and thereafter
in the systemic circulation, thus continuously promoting a
S. F. Assimakopoulos and D. Dimitropoulou have contributed equally
to this review.
S. F. Assimakopoulos (&)
D. Dimitropoulou

M. Marangos
C. A. Gogos
Department of Internal Medicine, Division of Infectious
Diseases, University Hospital of Patras, 26504 Patras, Greece
e-mail: sassim@upatras.gr
local and systemic inflammatory response. This chronic
immune activation is associated with HIV disease pro-
gression, suboptimal response to HAART and development
of non-AIDS comorbidities.
Conclusions We have reached a point where the effective
control of HIV viremia by HAART should be combined
with emerging pharmacological approaches aiming at the
restoration of the intestinal barrier, targeting its diverse
levels of structure and function. Elimination of the MT
phenomenon would mitigate its effect on immune
homeostasis, which might improve the prognosis of the
HIV-infected patient in terms of morbidity and mortality.
Keywords HIV
AIDS
Intestinal barrier
Intestinal
permeability
Microbial translocation
Bacterial
translocation
Endotoxemia
Introduction
The current pathogenetic aspects on HIV infection high-
light the importance of a chronic immune activation ulti-
mately leading to T lymphocyte homeostasis disruption
and immune deregulation associated with disease mani-
festations and progression [1–3]. It is currently widely
accepted that chronic immune activation in HIV infection
is to a great extent dependent on the pathological microbial
translocation (MT) of intestinal microbes or their products
from the gastrointestinal tract to portal and systemic cir-
culation [3, 4]. This pathological MT has been repeatedly
confirmed in experimental and clinical HIV infection, takes
place even from the early phase of acute infection and
throughout the course of chronic disease, and has been
associated with HIV disease progression, response to
treatment and non-AIDS comorbidities [5–7].
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The intestinal barrier: a brief overview
The intestinal epithelium has a complex role as it allows
absorption and excretion of substances necessary for body
homeostasis and at the same time acts as a barrier to var-
ious pathogens and their products. The gut barrier function
consists of three major lines of defense [8]: (a) the bio-
logical barrier, which is made up of normal intestinal flora
responsible for colonization resistance; (b) the immune
barrier, composed of locally acting factors such as secre-
tory IgA, intra-mucosal lymphocytes, Payer’s nodules,
mesenteric lymph nodes and the systemic host defense
represented mainly by the reticuloendothelial system; and
(c) the mechanical barrier, consisting of the closed-lining
intestinal epithelial cells and the capillary endothelial cells.
The epithelial and endothelial cells come into the closest
possible contact in the most apical part of the lateral cell
membranes (‘‘kissing points’’) by specific structures named
‘‘tight junctions’’ (TJs), which interconnect the cells and
restrict the passage of ions, molecules and cells through the
paracellular space [8, 9].
The intestinal barrier in HIV infection
HIV and the intestinal biological barrier
The specific composition of the gut microbiome exerts
many immunologic, metabolic and structural functions that
are essential to maintain gut barrier integrity [10]. Previous
studies on HIV-infected patients have demonstrated the
presence of quantitative and qualitative alterations of their
gut microbiota [11, 12]. Bifidobacteria and lactobacilli,
which have been shown to have a positive impact on
mucosal immune function and barrier integrity, were found
at significantly lower levels in HIV-infected patients as
compared to healthy subjects. On the other hand, oppor-
tunistic pathogens such as Pseudomonas aeruginosa and
Candida albicans, were detected at significantly increased
numbers in the vast majority of HIV-infected patients.
Most importantly, this impairment of the normal bowel
flora was present even from the early stages of HIV
infection and was associated with elevated levels of
intestinal inflammatory parameters detected in stools, such
as fecal calprotectin, indicating a possible correlation of
disrupted gut microecology with intestinal inflammation,
mucosal damage and mucosal immune activation [11, 13].
HIV and the intestinal immune barrier
The intestine which is the largest single immunological
organ of the body consists one of the initial targets of HIV,
resulting in the disruption of the intestinal immune barrier
123
S. F. Assimakopoulos et al.
even from the early stages of HIV infection. This is related
to the fact that most of the CD4? T cells of the intestine
are CCR5? activated memory CD4? T cells which are
preferred cellular targets for HIV [14, 15]. Depletion of
intestinal CD4? CCR5? T cells continues throughout the
chronic phase of the disease to a greater extent in the
intestinal tissue as compared to blood and lymph nodes
[16].
The Th17 cells, which are subpopulations of CD4? T
cells producing IL-17, exert pivotal role in the prevention
of MT by stimulating epithelial cell proliferation and
antibacterial defensin expression and by recruiting neu-
trophils to the gut-associated lymphoid tissue to clear
pathogens and their bioproducts [17, 18]. In HIV infection,
the early and massive loss of Th17 cells from the intestinal
mucosal epithelium has been proposed as an important
promoter of MT [19]. Previous studies have additionally
shown that not only the loss of Th17 cells, but also the
increased presence of CD4? FoxP3? Tregs might con-
tribute to the breakdown of the intestinal barrier integrity
[20]. The selective depletion of Th17 cells from the
intestinal mucosa in HIV infection could be explained
either by a direct cytotoxic effect of HIV in this cell pop-
ulation or by the inhibitory effect of proinflammatory
cytokines and in particular of IFN-c on Th17 cells devel-
opment, which is exerted with a concurrent promoting
action on Treg differentiation, thus altering the intestinal
immune cell balance [20].
Additionally, a recent study demonstrated the important
role of mucosal macrophages in the maintenance of gut
epithelial barrier integrity. It was found that the intestinal
mucosa of untreated HIV-infected patients was signifi-
cantly infiltrated by macrophages secreting proinflamma-
tory cytokines that may promote epithelial injury [21].
Moreover, the phagocytic activity of the accumulated
intestinal mucosa macrophages was significantly impaired
contributing to the development of the MT phenomenon
[21].
HIV and the intestinal mechanical barrier
Histologically, HIV infection, especially in its chronic
phase, induces morphologic changes in the intestinal
mucosa on routine light microscopy mainly represented by
villous atrophy [22, 23]. In addition, there is currently
evidence of important cellular (increased epithelial apop-
tosis) and paracellular (altered tight junction expression)
alterations that might contribute to the barrier defect of the
intestinal epithelium associated with HIV infection [7, 22].
Increased epithelial apoptosis seems to be an early
intestinal alteration in HIV infection as it has been detected
in patients with acute HIV infection [22]. Increased
expression of genes related to immune activation and
HIV and intestinal barrier
decreased expression of genes related to epithelial repair
have been associated, as a contributing underlying mech-
anism, with increased intestinal apoptosis through a cas-
pase-3 dependent pathway [24]. A variety of
immunological triggers, such as increased infiltration of
intestinal mucosa by perforin-expressing cytotoxic T lym-
phocytes in acute HIV infection and their loss in later
stages, increased production of proinflammatory cytokines
and activation of Fas on enterocytes and Fas-ligand on
lamina propria lymphocytes, have been associated with
increased intestinal epithelial apoptosis in HIV infection
[24–27]. A recent study demonstrated also that the HIV-1
transactivator factor (Tat) induces enterocyte apoptosis
through an oxidative stress-mediated mechanism [28].
Regarding the intestinal paracellular barrier, the first
observations on the detrimental effects of HIV infection on
enterocytes’ TJs come from in vitro experiments. Specifi-
cally, in colonic epithelial cell culture models, incubation
with the HIV-1 or its envelope glycoprotein (gp) 120 resulted
in decreased transepithelial electrical resistance associated
with downregulation of the key TJ molecular components
occludin and claudins -1, -2 and -4 [29, 30]. A potential
mechanism might be the increased production of TNF-alpha,
IL-6, IL-8 and other inflammatory cytokines from epithelial
cells when exposed to the HIV envelope glycoprotein, which
subsequently exert a detrimental effect on TJs’ structure and
function [29, 31]. In addition, the T84 enteric cell line when
exposed to HIV-1 displayed disruption of the ZO-1, which is
a macromolecule located underneath the TJs in the ‘‘tight
junctional plaque’’ serving a key role in bringing several
components of the tight junctional plaque with TJs and the
cytoskeleton [29]. It is hypothesized that gp120, after bind-
ing to the HIV co-receptor Bob/GPR15, which is abundant at
the basal surface of small intestinal epithelium, induces
microtubule loss via a calcium-dependent signaling pathway
[32]. The causative interrelation of HIV with intestinal epi-
thelial cells TJs’ disruption was proven by restoration of the
TJs structure and function with administration of gp120
neutralizing antibodies [29].
Intestinal barrier dysfunction, immune activation
and clinical implications for HIV infection
Pathogenetic link of intestinal barrier dysfunction
and immune activation
A number of previous studies have demonstrated that HIV
infection is associated with pathological MT due to intes-
tinal barrier integrity disruption. Specifically, it has been
shown that HIV-infected patients present significantly
increased levels of circulating lipopolysaccharide (LPS)
compared to uninfected controls [3, 33, 34]. The
953
phenomenon of pathological MT in HIV infection has been
additionally confirmed by the use of diverse other markers
of MT, such as the plasma levels of soluble CD14 (sCD14),
endotoxin core antibodies measured by the EndoCAb assay
and bacterial 16s rDNA, all of which were found elevated in
HIV-infected patients [35–37]. The extent of damage to the
epithelial barrier and the magnitude of MT, measured as the
amount of LPS within the underlying mucosa or the extent
of translocated microbial products in draining and remote
lymph node tissues, are positively correlated [34, 38].
HIV infection is characterized by persistent immune
activation even in phases of viral load decline such as after
the acute phase of infection or during administration of
suppressive anti-retroviral therapy [39, 40]. Persistent
immune activation is evidenced by the presence of activated
phenotypes of macrophages, cytokinemia (TNF-a, IL-6),
increased acute phase proteins (C- reactive protein) and
increased elements of the coagulation cascade (d-dimmers,
tissue factor). Regarding the adaptive immune system,
previous studies have demonstrated increased turnover and
exhaustion of T cells, low thymic output, increased turnover
of B cells and hyperimmunoglobulinemia [41–43].
The phenomena of pathological MT and persistent
immune activation in HIV infection are closely interrelated
according to the results of previous studies. Specifically, it
has been demonstrated that a significant correlation exists
between the magnitude of endotoxemia, used as a marker
of MT, and diverse indices of innate and adaptive immu-
nity, such as plasma IFN-a and T cell activation levels [33,
35–37, 44]. There are two main theories of how MT can
lead to immune activation. The first one supports the view
that after the disruption of the intestinal barrier integrity,
intestinal bacteria and endotoxins translocate in mesenteric
lymph nodes as well as in portal circulation, thereafter
entering into the systemic circulation and thus invading
normally sterile extraintestinal tissues [45]. This process
causes systemic infections and promotes a systemic
inflammatory response syndrome. The second theory sup-
ports that, after the disruption of gut barrier integrity,
bacteria and endotoxins cross the mucosal barrier and
activate an intestinal inflammatory response, even when
these translocating factors are trapped within the gut wall
or intestinal lymph nodes and do not reach the systemic
circulation [46]. According to later view, the gut becomes a
proinflammatory organ and gut-derived inflammatory fac-
tors, carried mainly in the mesenteric lymph, induce a
systemic inflammatory response with detrimental effects in
multiple organs’ structure and function [47].
Clinical implications
In HIV infection, the continuous immune activation driven
by the phenomenon of pathological MT exerts a pivotal
123
954
pathophysiological role in disease progression [48]. In
particular, MT promotes the proliferation of activated T
cells which in turn provide new targets for HIV infection,
leading to further impairment of the immune function
through T and B cell dysfunction with subsequent poor
control of pathogens and further priming of immune
123
S. F. Assimakopoulos et al.
activation [7, 49]. In addition, MT and its associated
chronic immune activation in HIV infection seem to exert
an important role in diverse non-AIDS comorbidities.
HIV infection is a major cause of acceleration of hep-
atitis C virus-related liver disease, cirrhosis and death [50,
51]. The most widely proposed mechanisms implicated in
 HIV and intestinal barrier
b Fig. 1 Overview of intestinal barrier dysfunction in HIV infection
and interconnection with chronic immune activation: HIV infection
induces a multifactorial disruption of intestinal barrier integrity by
negatively affecting all of its major levels of defense. a Gut
microecology is altered allowing overgrowth of pathogenic bacteria
with consequent increase of luminal endotoxin load. b The intestinal
immune barrier is significantly impaired through depletion of CD4(?)
T cells, especially Th17 cells. Immune dysregulation is also
evidenced by increased CD4? FoxP3? Tregs and increased infiltra-
tion of lamina propria by mucosal macrophages, which however
present decreased phagocytic capacity. c The integrity of the
intestinal mechanical barrier, which comprises the intestinal epithelial
cells and their close interconnections (tight junctions––TJs), is
disrupted; HIV alters the expression of enterocytes’ TJs thus opening
the paracellular route and additionally promotes the apoptotic death of
intestinal epithelial cells. Pathogenic microbes and LPS from the
intestinal lumen pass through the disrupted mechanical barrier to the
lamina propria, where they cannot be cleared by the dysfunctional
immune system. Intestinal macrophages are activated to produce
proinflammatory cytokines and reactive oxygen species. This inflam-
matory and oxidative environment further promotes apoptotic
epithelial cell death and disrupts the structural and functional
integrity of enterocytes’ TJs, while further aggravating the defects
of the local immunological defense by altering the intestinal immune
cell balance through inhibition of Th17 cells development and
promotion of Treg differentiation. More microbes and LPS can now
escape the intestinal lumen and gain access to the systemic
circulation, where they induce a systemic inflammatory response
associated with HIV clinical progression, suboptimal CD4(?)T cell
recovery on ART and with development of non-AIDS comorbidities
from diverse systems
the acceleration of liver injury in HIV/HCV co-infection
are increased liver expression of profibrogenic cytokines,
increased hepatic oxidative stress and hepatocellular
apoptosis. Pathological MT and immune activation in the
setting of HIV infection seem to exert a pivotal role in the
induction of the above-stated alterations [52–54]. Gut-
derived translocating bacteria and/or their products might
promote liver fibrosis either by directly interacting with
Kupffer cells and hepatic stellate cells or indirectly through
induction of systemic immune activation and promotion of
hepatocellular apoptosis [52–55].
Also, according to previous clinical studies, MT and its
associated persistent immune activation and proinflamma-
tory state have been associated with dyslipidemia, insulin
resistance and cardiovascular complications in HIV-infec-
ted patients [56]. Another very recent study examined
plasma LPS and sCD14 levels in untreated and treated HIV
patients and correlated these with metabolic indices [57]. In
the whole group of patients, plasma LPS levels were neg-
atively correlated with large particle HDL levels and posi-
tively correlated with triglyceride levels, while sCD14 was
negatively correlated with HDL cholesterol levels. These
findings imply that MT possibly contributes to the increased
cardiovascular disease risk observed during HIV infection.
Patients with HIV infection are at markedly increased
risk for the development of multiple subtypes of non-
955
Hodgkin’s lymphoma [58, 59]. Among contributing
mechanisms, chronic immune activation seems to exert an
important role. It has been previously shown that markers
of immune activation, such as IL-6, IL-10, CRP, sCD23,
sCD27 and sCD30, are elevated several years preceding the
diagnosis of AIDS-associated non-Hodgkin lymphoma
[60]. Considering the pivotal pathophysiological role of
MT in chronic immune activation, a recent study demon-
strated that elevated serum markers of MT, such as LPS
and sCD14, are significantly associated with increased risk
for non-Hodgkin lymphoma development, supporting an
etiologic role for MT in lymphomagenesis among HIV-
infected individuals [61].
Chronic immune activation seems to be a key mecha-
nism in the pathogenesis of HIV-associated neurocognitive
disorders as well [62]. Activated monocytes can traffic the
HIV virus into the central nervous system and then infect/
activate other macrophages or other cell types [62].
Infected macrophages represent the major cell type sup-
porting productive HIV infection in the brain. Also,
infected or activated macrophages can release numerous
neurotoxic factors which have been implicated in the
pathogenesis of HIV-associated neurocognitive impairment
such as HIV proteins, cytokines and chemokines [63]. The
gut-derived bacterial products (LPS) can trigger monocyte
activation via CD14 and TLR4-mediated signaling [64]. A
recent study demonstrated that plasma LPS and sCD14
levels predict the development of HIV-associated dementia
independently of viral load, suggesting the important role
of MT in the pathogenesis of HIV-associated dementia
[65].
Interventions for prevention of HIV-associated
intestinal barrier dysfunction and MT
HAART
Numerous previous studies have shown that HAART,
despite the effective clearance of plasma HIV-1 RNA to
undetectable levels, only partly decreases plasma levels of
diverse markers of MT and immune activation [3, 23, 66–
68]. According to previous studies, the potential beneficial
effect of HAART on the intestinal barrier function might
be based on restoration of enterocyte TJ proteins’ expres-
sion, thus increasing the transepithelial electrical resistance
of the intestinal mucosa, and on intestinal mucosal CD4?
T cell reconstitution, especially when HAART is instituted
early [23, 67]. With regard to other parameters of intestinal
mucosal immunity such as CD8? function, NK cell
reconstitution, immunoglobulin production and lymphatic
tissue architecture, overall HAART seems to support par-
tial mucosal immune recovery [67].
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Beyond HAART interventions
Beyond HAART, a number of other preventive treatment
strategies have a reasonable basis for use in HIV infection
aiming at elimination of MT, either by strengthening the
above-described diverse levels of gut barrier integrity or by
eliminating the burden of translocated bioproducts by act-
ing before or after their escape from the gut lumen.
Interventions aiming at enhancing the intestinal barrier
integrity
i. Restoration of the intestinal biological barrier.
Maintenance of the gut microecology could exert beneficial
effects on preservation of enterocyte homeostasis and pre-
vention of mucosal immune activation. A number of clini-
cal studies have shown that supplementation with probiotics
prevents intestinal hyperpermeability in diverse pathologi-
cal conditions [69–72]. In HIV-1 infection probiotics were
shown to exert beneficial effects in children who become
infected before the development of a normal gut flora and
are at risk for chronic immune activation and growth
abnormalities, while HIV-1-infected adults consuming
probiotic-enriched yogurt presented a significant increase of
CD4 cells compared to patients not consuming yogurt [73].
ii. Restoration of the intestinal immune barrier.
Disruption of T cell homeostasis in the intestinal
immune system is a cardinal feature of HIV infection.
Given that IL-7 is an essential cytokine for T cell devel-
opment and homeostasis, a recent clinical study examined
the effect of recombinant IL-7 administration on the gut-
residing naı̈ve and memory CD4(?) T cells in HIV-
infected patients on HAART with inadequate CD4? T cell
recovery with promising results [74].
iii. Restoration of the intestinal mechanical barrier.
Considerable experimental and clinical evidence sug-
gests that enteral immunonutrition using glutamine, argi-
nine and omega-3 fatty acids exerts beneficial effects on
preservation of gut barrier integrity against diverse injuri-
ous insult [75, 76]. The enhancement of intestinal perme-
ability by glutamine may be explained by its antiapoptotic
effect on the intestinal mucosa [77]. A recent study dem-
onstrated that nutritional supplementation with glutamine
in HIV-infected patients improved intestinal barrier func-
tion [78]. In addition, considering the fact that oxidative
stress has been implicated in intestinal injury in HIV
infection, previous studies demonstrated that administra-
tion of the antioxidants N-acetyl-cysteine or monosodium
luminol prevent intestinal barrier disruption in HIV infec-
tion [28, 79].
123
S. F. Assimakopoulos et al.
Interventions aiming at the translocating microbial and/
or endotoxin burden pre- or post-translocation
i. Elimination of the gut luminal bacteria and/or their
bioproducts before their translocation.
Elimination of the intestinal bacterial and/or endotoxin load
could be achieved by oral administration of non-absorbed
antibiotics such as rifaximin [80]. However, the need for
long-term intervention in HIV infection carries the risk for
antibiotic-resistant bacteria selection. Another option,
simple in its conception and relatively safe, is elimination of
luminal endotoxin load by oral lactulose administration.
Lactulose exerts endotoxin-binding capacity, thus neutral-
izing before translocation this important pathophysiological
trigger for chronic immune activation in HIV infection. A
disadvantage of this second option is the diarrheal effect of
lactulose that could limit its clinical application, especially
in HIV-infected patients with associated chronic diarrhea.
ii. Clearance of the systemically translocated bacterial
bioproducts.
The bactericidal/permeability-increasing protein is a
naturally occurring endotoxin-binding protein produced in
neutrophils, eosinophils and some epithelial cells, which
binds endotoxin, neutralizing the activity and inhibiting
cytokine production by mononuclear cells. Animal studies
with models of systemic endotoxemia have shown that this
compound reduces the endotoxin-induced mortality to a
death rate comparable to non-endotoxemic experimental
animals. The rationale for its potential use in HIV-infected
patients is further strengthened by its demonstrated defi-
ciency in this patient population [81].
Conclusions
HIV infection disrupts the integrity of the intestinal bio-
logical, immune and mechanical barrier, promoting the
phenomenon of microbial translocation which is a crucial
determinant of chronic immune activation (Fig. 1). To our
opinion, we have reached a point where the effective
control of HIV viremia by HAART should be combined
with emerging pharmacological approaches aiming at the
restoration of the intestinal barrier targeting its diverse
levels of structure and function. Elimination of the MT
phenomenon would mitigate its effect on immune
homeostasis, which might improve the prognosis of the
HIV-infected patient in terms of morbidity and mortality.
Conflict of interest On behalf of all authors, the corresponding
author states that there is no conflict of interest.
HIV and intestinal barrier
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