Download Review The pathogenesis of liver disease in the setting of HIV

Antiviral Therapy 14:155–164
Review
The pathogenesis of liver disease in the setting of
HIV–hepatitis B virus coinfection
David M Iser1,2 and Sharon R Lewin2,3*
Department of Medicine, The University of Melbourne, St Vincent’s Hospital, Melbourne, Victoria, Australia
Infectious Diseases Unit, The Alfred Hospital, Melbourne, Victoria, Australia
3
Department of Medicine, Monash University, Melbourne, Victoria, Australia
1
2
*Corresponding author: E-mail: [email protected]
There are many potential reasons for increased liver­related mortality in HIV–hepatitis B virus (HBV) coinfection compared with either infection alone. HIV infects
multiple cells in the liver and might potentially alter
the life cycle of HBV, although evidence to date is limited. Unique mutations in HBV have been defined in
HIV–HBV-coinfected individuals and might directly alter
pathogenesis. In addition, an impaired HBV-­specific
T-cell immune response is likely to be important. The
roles of microbial translocation, immune activation and
increased hepatic stellate cell activation will be important areas for future study.
Introduction
Approximately 370 million people worldwide are
infected with the hepatitis B virus (HBV) and approximately 40 million with HIV (6% and 0.6% of the
world population, respectively) [1]. Areas endemic for
HBV, such as sub-Saharan Africa and Asia, also have a
high prevalence of HIV. Approximately 5–10% of individuals with HIV are coinfected with HBV [2], but this
could be as high as 20% in parts of Africa [3].
The presence of HIV has important effects on the
natural history of HBV. Individuals with HIV–HBV
coinfection clear acute HBV less frequently, seroconvert from hepatitis B e antigen (HBeAg) to hepatitis B
e antibody less frequently [4], have higher HBV DNA
levels [5], lower levels of alanine aminotransferase
(ALT) and milder necroinflammatory activity on histology than those with HBV alone [5]. Progression to
cirrhosis, however, seems to be more rapid and more
common and liver-related mortality is higher in HIV–
HBV coinfection than with either infection alone [6]. In
this article we review the current understanding of how
these two viruses interact (Figure 1) and highlight areas
where we believe further research is needed.
Viral factors
HIV in vivo studies
There are numerous studies demonstrating evidence for
the presence of HIV within liver tissue (reviewed in [7]).
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Lewin.indd 155
HIV capsid antigen (p24) has been demonstrated within
Kupffer cells by immunohistochemistry in liver from
HIV-positive individuals [8,9]. In addition, HIV DNA
was detected by PCR and HIV RNA detected by in situ
hybridization in liver obtained from HIV-infected individuals following percutaneous biopsy, surgical biopsy
and autopsy. HIV RNA was detected in Kupffer cells
and other sinusoidal cells, portal mononuclear inflammatory cells and hepatocytes [9,10]. In one study that
measured HIV DNA in liver samples from individuals coinfected with HBV, the authors observed a trend
towards higher amounts of HIV in liver from individuals who were also HBV-infected compared with those
without HBV infection, although this difference did not
reach statistical significance [9].
HIV in vitro studies
In vitro studies of HIV infection of liver cells support
the in vivo findings (Table 1). HIV infection of primary
human Kupffer [11,12] and primary endothelial cells
has been demonstrated in vitro [13]. A number of studies have demonstrated HIV infection of hepatoma cell
lines as models for primary hepatocytes. These studies have included cell lines such as Huh-7, Hep3B,
CZHC/8571, PLC/PRF/5 (Alexander cells) and
hepatoblastoma-­derived HepG2 [14]. Infection was
confirmed by detecting reverse transcriptase or p24 in
culture supernatant, in situ hybridization for messenger
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DM Iser & SR Lewin
Figure 1. Pathogenesis of liver disease in HIV–HBV coinfection
HBV
HSC activation
• High viral load
• Mutations
Drug resistance
(L173V+L180M+M204V)
•
Inflammation
•
Hepatic fibrosis
Unique (-1G)
Intrahepatic HIV
• KC
HC
• HC
Gut
• HSC
• Mucosal
Portal vein
• EC
CD4+ T-cells
• Microbial
trafficking
• LPS burden
EC
HSC
KC
Immune system
Hepatocyte
Clinical factors
damage
• HBV-specific CD4+ and
CD8+ T-cells
• CD4+/CD8+ T-cell ratio
• HAART
• NK cell activity
• Alcohol
• TLR-2 expression (HBeAg)
• Other medication
Potential factors leading to the progression of liver disease in HIV–hepatitis B virus (HBV) coinfection. HIV-infected cells are indicated in red. EC, endothelial cells;
HAART, highly-active antiretroviral therapy; HBeAg, hepatitis B e antigen; HC, hepatocytes; HSC, hepatic stellate cells; KC, Kupffer cells; LPS, lipopolysaccharide (from
bacterial cell walls); NK, natural killer; TLR, Toll-like receptor.
RNA and radioimmunoassay for HIV type-1 antigens.
Virions were also seen under electron microscopy. Infection was thought to be CD4-­independent, as all five cell
lines were negative for CD4 receptors by immunofluorescence, for CD4 messenger RNA by slot-blot hybridization and because infection was demonstrated despite
the presence of soluble CD4 or anti-CD4 monoclonal
antibody. In another study, HepG2 cells were found to
express CD4 and could be infected with HIV [15]. PLC/
PRF/5, CZHC/8571 and Hep3B constitutively express
hepatitis B surface antigen (HBsAg) and might therefore be useful models for investigating coinfection of
HIV and HBV in vitro.
A recent study from the Mayo Clinic demonstrated the
presence of CXCR4 on human hepatocytes and proposed
that HIV might cause hepatocyte apoptosis by signalling
through CXCR4 without actually infecting the cell [16].
Although HIV usually gains entry to target cells via CD4
receptors in conjunction with either coreceptor CXCR4
or CCR5, there are a number of other coreceptors that
can be employed. These include CCR3, CCR2b, CCR8,
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Apj, Strl33, Gpr1, Gpr15, CXCR1, ChemR23 or RDC1
[17]. It is not clear whether these alternative receptors are found on hepatocytes or other liver cells. HIV
infection of CD4 hepatic cells might occur via receptormediated endocytosis or via alternative receptors. Such
mechanisms have been proposed for HIV infection of
astrocytes, which are also CD4-negative [18].
HIV infection of hepatic stellate cells (HSCs) has also
recently been reported, using both primary HSCs and
the LX-2 cell line [19]. Primary HSCs and LX-2 cells
express CD4 receptors and the HIV coreceptors CCR5
and CXCR4 [19–21]. However, HIV infection of HSCs
appeared to be independent of CD4, and was reduced
in the presence of endocytosis blockers, chlorpromazine
and NH4Cl [19]. HSCs infected with HIV or exposed
to gp120 showed increased activation and fibrogenesis,
as measured by a-smooth muscle actin (α-SMA) and
collagen production, and increased levels of monocyte
chemotactic protein-1 (MCP-1). These findings could
provide an explanation for the increased fibrosis seen
in HIV–HBV-coinfected individuals [5].
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Liver disease pathogenesis in HIV–HBV coinfection
Hepatitis B virus mutations
HBV itself is not usually pathogenic [22]; however,
a form of fulminant hepatitis called fibrosing cholestatic hepatitis (FCH) has been described in the posttransplant setting and in HIV–HBV coinfection [23]. In
HBV-monoinfected individuals, FCH is characterized
by extremely high levels of HBV DNA, high levels of
expression of hepatitis B core antigen and HBsAg in
hepatocytes and mild inflammatory activity [24]. However, despite extremely high HBV DNA levels seen in
HIV–HBV coinfection [5], only a single case of FCH has
been reported [23]. The preservation of residual antiHBV immune pressure, even in advanced AIDS, might
be enough to prevent the occurrence of FCH [25].
A novel -1G deletion mutant was reported recently in
HIV–HBV-coinfected individuals, which might be associated with altered HBV pathogenesis by two proposed
mechanisms [26]. Firstly, the mutation led to a premature stop codon and truncation of the HBV precore and
core genes, and might be associated with increased replication, as described in HBV-monoinfected individuals
following renal transplant [27]. Secondly, the stop codon
occurred within a known major histocompatibility complex (MHC) class II-restricted epitope, and might therefore represent an escape mutation. However, it remains
unclear why immune escape would occur in the setting
of immunosuppression and an impaired HBV-specific
CD4+ T-cell response [28]. In addition to the -1G mutation, a number of other mutations were identified in the
core/precore and polymerase genes, hepatitis B X protein (HBx) and regulatory sequences [26]. Some of these
mutations, such as core mutation cI59V, were detected
exclusively in HIV–HBV-­coinfected individuals, whereas
cL60I was also found in HBV-­monoinfected individuals.
Both these mutations occurred in the same CD4+ T-cell
epitope as the -1G mutation, and might also be related
to immune escape.
In individuals on long-term immunosuppression
following liver transplant, complex mutations in the
core promoter, core gene and pre-S region have been
described [29]. Deletions in the core gene can enhance
replication at the level of pregenomic encapsidation or
reverse transcription when in the presence of an adequate supply of wild-type core protein [30]. Deletions in
the pre-S region might be associated with accumulation
in the hepatocytes of surface protein via alteration in
transcriptional regulation [31]. This has been shown to
be associated with increased hepatocyte destruction in
transgenic mice, either via direct toxicity or via immune
or cytokine mediated injury. It is possible that similar
mutations that lead to increased hepatocyte destruction
might occur in HIV–HBV coinfection, although to date
this has not been demonstrated.
Hepatitis B virus drug resistance
Highly active antiretroviral therapy (HAART) that
targets HBV in HIV–HBV coinfection can promote
the selection of isolates with mutations in the HBV
polymerase [25]. Lamivudine resistance in HIV–HBV
coinfection is extremely common with >90% of individuals developing resistance after 4 years of treatment
[32]. This is in contrast to the infrequent emergence of
HBV resistance to tenofovir [33].
Following prolonged treatment with lamivudine, a
triple HBV polymerase mutant (rtL173V+rtL180M+
rtM204V) has been described in both HBV-monoinfected and HIV–HBV-coinfected individuals [34]. This
combination of mutations might have significant public
health implications, as it has reduced binding to hepatitis B surface antibody (HBsAb) and therefore could
potentially act as a vaccine escape mutation [35]. A high
prevalence (17%) of this triple HBV mutant was found
in HBV viraemic individuals coinfected with HIV who
had received lamivudine for prolonged periods [32].
A number of studies in HBV monoinfection have
shown that drug resistance can be prevented with
combination therapy [36,37]. Combination therapy
with adefovir and lamivudine for lamivudine-resistant HBV was associated with low rates of the adefovir-resistant mutation rtA181V (4% after 4 years)
Table 1. Evidence that HIV is able to infect liver cells from in vitro studies using either primary human cells or liver-derived cell lines
Affected cells
Method of HIV detection
Mechanism
Primary liver cells
Kupffer cells
RT in SN, EM, IF CD4-dependent
Endothelial cells
RT and p24 in SN, EM, IF SN infective to T-cell line
CD4-dependent
Hepatic stellate cells
RT and p24 in SN
CD4-independent
Hepatocytes
Effect of gp120 only (no infection)
CXCR4-mediated
Liver-derived cell lines
Hepatoma (Huh7, Hep3B and Alexander cells)
RT and p24 in SN, mRNA (in situ hybridization), RIA
CD4-independent
Hepatoblastoma (HepG2 cells)
p24 in SN
CD4-dependent
Stellate cell lines (LX-2 cells)
RT, p24
CD4-independent
Reference
[11,12]
[13]
[19]
[16]
[14]
[15]
[19]
EM, electron microscopy; IF, immunofluorescence; mRNA, messenger RNA; RIA, radioimmunoassay; RT, reverse transcriptase; SN, supernatant.
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DM Iser & SR Lewin
and no virological breakthrough over a median of 42
months in 145 individuals [37]. Adefovir resistance
has been reported at much higher rates (22% after
2 years) in individuals treated with adefovir monotherapy for lamivudine-­resistant HBV [38]. A recent
randomized study of lamivudine, tenofovir or lamivudine plus tenofovir in 36 HIV–HBV-coinfected individuals initiating HAART demonstrated significantly
higher rates of drug resistance and persistent viraemia
at 48 weeks in individuals receiving lamivudine alone
compared with individuals receiving tenofovir either
alone or in combination with lamivudine [39].
HBV resistance to tenofovir remains rare as reported
from a number of retrospective studies of HIV–HBVcoinfected cohorts (summarized in [40]). A potential
unique tenofovir-resistant mutation, rtA194T, was
described in only one patient from these cohorts,
in association with two lamivudine-resistant mutations, rtL180M and rtM204V [41]. Small numbers of
patients in many of these cohorts have experienced
persistent HBV viraemia or significant rebounds in
HBV DNA despite adherence to tenofovir and without
any detectable tenofovir-resistant mutations [33,40].
HIV and HBV interactions in vitro
Very few studies have examined the direct effects of
HIV on HBV replication or vice versa. HBx has been
shown to enhance transcription of the HIV long terminal repeat in Jurkat T-cells [42]. This interaction is
probably mediated via the HIV κB-like transcriptional
enhancer sequence in the long terminal repeat [43], or
alternatively via an interaction with the HIV tat gene
[44]. Some effects of accessory HIV proteins on HBV
promoter/enhancer elements have been found, but none
have been able to explain increased HBV replication.
Pseudotyped viruses containing full-length HIV and
combinations of large (L), medium (M) and small (S)
HBsAg were created by cotransfecting 293T cells.
Infectivity was assessed on primary human hepatocytes
as well as cell lines (HepG2 cells and HuH7 cells) [45].
HIV (L, M and S) infected primary hepatocytes but
none of the cell lines, whereas HIV (S), which lacks the
pre-S1 domain, did not infect primary hepatocytes. This
finding implies that HBsAg might potentially facilitate
HIV entry of primary hepatocytes.
Immune factors
Anti-hepatitis B virus response
The likelihood of a successful immune response to
infection with HBV varies depending on age at the
time of infection. Clearance of HBV DNA and seroconversion from HBsAg to HBsAb is much more
likely in adulthood than childhood [46]. HBsAg seroconversion is significantly less likely in the presence of
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HIV coinfection [47]. Immune factors necessary for
successful clearance of acute HBV are not completely
understood, but involve both cellular and humoural
arms of the adaptive immune response, as well as the
innate immune response (reviewed in [48]).
Innate immune response
The earliest response to HBV is likely to depend on the
innate immune system, including Toll-like receptors
(TLRs) and the release of interferon (IFN)-γ and IFN-β
from hepatocytes [48–50]. These cytokines recruit antigen-presenting cells, such as Kupffer cells, which might
induce hepatic injury during HBV infection via expression of Fas ligand [51]. Natural killer (NK) cells (CD3and CD56+) and NK T-cells (CD3+ and CD56+) are also
recruited, and might be important in the initial anti-HBV
response [52]. These components of the innate immune
response are important prior to an effective adaptive
immune response [48]. Reduced NK-cell-­mediated cytotoxicity has been reported in HIV infection, as well as
in acute HBV infection in both HIV-positive and HIV­negative individuals [53]. Conversely, markedly increased
NK-cell-mediated cytotoxicity was seen in one individual
who died of fulminant hepatic failure from acute HBV
infection in the setting of AIDS [53].
Altered TLR expression and function might also
be important in response to HIV and HBV infection.
TLR expression and function is significantly altered
by HIV infection [54], which might be important in
immune activation and response to other pathogens,
including HBV. In HBV, decreased TLR-2 expression on hepatocytes, Kupffer cells and peripheral
monocytes has been described in individuals with
HBeAg-positive chronic hepatitis B (CHB) compared
with HBeAg-negative and uninfected controls [49].
Decreased TLR-2 expression and function (tumour
necrosis factor [TNF]-α production) were confirmed
in an in vitro model, whereas no change was observed
in TLR-4 expression. Both TLR-2 and TLR-4 expression in peripheral monocytes were decreased in
another cohort of individuals with CHB, compared
with uninfected controls [55]. Together, the findings
support a role for TLR in mediating HBV immune
tolerance and pathogenesis.
HBV might also affect maturation and function of
myeloid dendritic cells (mDCs). Both HBV virions and
HBsAg might reduce mDC maturation, T-cell stimulation and interleukin (IL)-12 production [56]. Similar
findings have been reported in other dendritic cell (DC)
subsets [57]. However, not all studies have found a
difference in mDC number, phenotype or function in
CHB. DCs do not appear to support active replication
of HBV [58]. By contrast, DCs in various tissues are an
important target of HIV and facilitate dissemination of
infection to T-cell populations [59]. Specific alterations
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Liver disease pathogenesis in HIV–HBV coinfection
in TLRs or in DC number or function in HIV–HBV
coinfection have not been reported to date.
Adaptive immune response
The adaptive immune response to HBV infection includes
HBV-specific CD8+ cytotoxic T-lymphocytes (CTLs)
and the production of non-cytolytic cytokines such as
IFN-γ, TNF-α and IFN-α/β [48,60,61]. HBV-specific
T-cell responses as well as non-HBV-specific T-cells are
both important [62]. An effective CTL response to HBV
needs to be both multispecific, where a number of different HBV epitopes can be recognised, and polyclonal,
meaning multiple T-cell receptors are able to bind a
given HBV peptide–MHC complex [63,64].
HBV-specific CTL responses are reduced in HIV­positive individuals with natural immunity to HBV, compared with HIV-negative individuals with resolved HBV
infection [65]. The HBV-specific CD4+ T-cell response is
also significantly diminished in HIV–HBV coinfection
compared with HBV-monoinfection [28]. Interestingly,
in some individuals with chronic HBV infection who
acquire acute HIV infection, there is a surprising decrease
in HBV DNA and HBeAg loss, possibly because of HIVinduced non-cytolytic cytokine release [66]. An increase
in both HBV-specific CD4+ and CD8+ T-cell responses
occurs after treatment with HAART [67].
The initial immune response to acute HIV infection
involves effector cells of both the innate and adaptive
immune responses, namely NK cells and HIV-specific
CD8+ T-cells [68]. The CD8+ T-cell response is particularly important, as it has been shown to exert selective
pressure driving mutations in key HIV-specific CD8+
T-cell epitopes [69]. HIV antibodies are also produced by the humoural arm of the adaptive response,
although their exact role is unclear. Host genetic factors are important determinants of immunological
control of HIV, particularly human leukocyte antigen
(HLA) molecules. For example, specific HLA alleles
might be associated with increased immunological
control (HLA-B57 and HLA-B27) or poorer outcome
(HLA-B35 and HLA-B22) [70].
Immune restoration disease
Following the initiation of HAART in individuals with
low CD4+ T-cell counts (<100 cells/µl), approximately
10–30% of individuals present with a new opportunistic infection or worsening clinical symptoms of an
already established infection [71], a condition that
is often referred to as immune restoration disease
(IRD). Hepato­toxicity (grade 3 or 4 transaminitis)
after HAART occurs more frequently in HIV-infected
individuals with either HBV or hepatitis C virus
(HCV) coinfection [72,73]. The aetiology of abnormal ALT levels or hepatic flare following the initiation of HAART is often multifactorial, and includes
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worsening of underlying liver disease, antiretroviral
hepatotoxicity, other medications and opportunistic
infections, as well as IRD [74,75].
The pathogenesis of HBV-related IRD is currently
unclear, but is possibly secondary to restoration of the
anti-HBV adaptive immune response often associated with
HBeAg seroconversion or a fall in HBV DNA [25,67,76].
Hepatic flare has also been reported without any changes
in HBV markers or DNA, and even an increase in HBV
DNA following HAART has been described [76,77]. A
recent report demonstrated increased levels of CXCL10,
MCP-1 and sCD30, cytokines and chemokines associated
with T-cell and NK recruitment to the liver, in individuals
with HBV-related IRD [75]. Important clinical risk factors
for HBV-related IRD are a high baseline HBV DNA level,
high ALT, low baseline CD4+ T-cell count and a rapid
rise in CD4+ T-cell count [76]. The risk of mortality or
significant morbidity appears to be higher in those with
underlying advanced liver disease [76]. HBV-related IRD
might also occur in the setting of occult HBV, particularly
in individuals who are HBsAg- and HBsAb-negative but
hepatitis B core antibody-positive [78].
Hepatic factors
Apoptosis
Apoptosis of liver cells, including hepatocytes and
HSCs, is central to the process of hepatic inflammation that leads to fibrosis. Apoptosis might be the
result of inflammation and fibrosis, but could also
augment these processes [79]. Two apoptotic pathways have been described: the extrinsic pathway via
death receptors (Fas, TNF receptor 1 and TNF-related
apoptosis-inducing ligand [TRAIL] receptors 1 and 2)
and the intrinsic pathway via intracellular organelles.
The intracellular domains of activated death receptors interact with initiator caspases (such as caspase
8) [80] converging with the intrinsic pathway via caspase 3 [79]. Intracellular processes leading to apoptosis
include changes in the endoplasmic reticulum, nuclear
DNA changes and mitochondrial dysfunction. This
might be a mechanism by which HIV or HAART could
increase hepatic apoptosis [81].
Activation of TRAIL receptors causes apoptosis by
the extrinsic pathway, as described earlier. An increase
in membrane-bound TRAIL associated with CD4+ and
CD8+ T-cells was found in peripheral blood from individuals with HBV compared with healthy controls,
and this correlated with disease activity (ALT levels
and liver histology) [82]. Recombinant human TRAIL
caused massive and rapid apoptosis and cell death to
>60% of human primary hepatocytes exposed for 10 h
[80]. Virally infected cells, but not uninfected cells,
were susceptible to TRAIL-mediated cytotoxicity in
vitro [83]. TRAIL was also found at high levels in NK
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cells in the blood and liver of individuals with HBV
and spontaneous hepatic flare [84].
The extrinsic pathway appears important for T-cell
mediated cytotoxicity, whereby all T-cell cytotoxicity
appears to be facilitated by either the Fas or perforin
pathways [85]. Altered T-cell numbers and a reduced
CD4/CD8 ratio in the setting of HIV infection could
cause increased hepatic apoptosis. Changes in apoptosis in HIV–HBV coinfection might be a crucial key to
explaining increased hepatic fibrosis; however, direct
evidence of this is lacking.
Fibrogenesis mediated by hepatic stellate cells
The major effector cells producing fibrosis are HSCs
[79]. HSCs can undergo transformation from a quiescent state to a myofibroblast. Once activated, HSCs are
important in the formation of the extracellular matrix
and collagen, as well as producing proinflammatory
cytokines and phagocytosing apoptotic bodies, which
are themselves fibrogenic [86]. HSCs can undergo
apoptosis either spontaneously, which is uncommon
in vivo [87], or via the death receptors, Fas [88] and
TRAIL receptor 2 [89].
Although a reduction in HSC numbers is important
in the resolution of liver disease, the expression of
death ligands, such as Fas, can be both proinflammatory and profibrogenic [90]. HSCs can also increase
inflammation via the expression of MCP-1, intracellular adhesion molecule-1 macrophage inflammatory protein-2 and the complement pathway [91].
HSC activation also leads to upregulation of TLR-4,
which is associated with the release of proinflammatory cytokines, such as IL-8 and MCP-1, via nuclear
factor-κB [92]. This might explain how bacterial cell
wall products, such as lipopolysaccharide (LPS) and
lipoteichoic acid cause HSCs to release cytokines, such
as IL-6 and MCP-1, and induce accelerated fibrosis
[93]. In addition, HBx has a direct effect on HSC
activation, leading to increased production of matrix
metalloproteinase-2, tissue growth factor (TGF)-β,
collagen-1 and α-SMA [94].
HSC activation might also depend on interaction with
different T-cell subpopulations [91]. Evidence from a
murine model suggests that CD8+ T-cells contribute to
more HSC activation than CD4+ T-cells or whole splenic
lymphocytes [95]. This might be relevant to HIV–HBV
coinfection, where the number of CD8+ T-cells is increased
relative to CD4+ T-cells, compared with HBV monoinfection. NK cells also interact with HSCs and might reduce
HSC cell numbers by inducing HSC apoptosis [91]. Subsets of NK cells are susceptible to HIV infection and NK
cells have reduced cytolytic activity and cytokine production in HIV infection [96]. NK cell suppression of
HSC activity might therefore be reduced in HIV–HBV
coinfection compared with HBV monoinfection.
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Microbial translocation, increased lipopolysaccharide
and generalized inflammatory response
All venous drainage from the gut flows via the portal
system to the liver, which is therefore a site of significant microbial traffic. Blood cultures performed at regular intervals immediately following percutaneous liver
biopsy have demonstrated subclinical transient bacteraemia with Gram-negative organisms [97]. Following
HIV infection, there is a profound loss of CD4+ T-cells,
DCs, NK cells and macrophages from gut-­associated
lymphoid tissue [98–100]. CCR5+ CD4+ T-cells are
significantly depleted, and there is associated T-cell
activation and collagen formation within lymph nodes
[98]. This damage to gut mucosal defence might lead to
increased circulating microbial products, as measured
by both LPS from bacterial cell walls and soluble CD14
(sCD14) from LPS-stimulated monocytes, and contribute to HIV-related systemic immune activation [99].
This increased microbial burden might cause immune
dysregulation and increased CD4+ T-cell loss via TLR
activation [101]. Partial improvement in levels of LPS
and sCD14 has been demonstrated following HAART,
suggesting an improvement in mucosal immunity and
reduction in microbial translocation [99].
Bacterial endotoxaemia has also been described in
other clinical settings, including decompensated cardiac
failure, septic shock and a range of liver diseases including alcoholic liver disease and cirrhosis [102]. In addition to increased levels of endotoxin in cirrhotic individuals, derangements in pro- and anti-inflammatory
cytokines might lead to relative endotoxin tolerance
and increased susceptibility to bacterial infection [103].
Individuals with acute (hepatitis A and B) and chronic
(hepatitis B and C) viral hepatitis were found to have
increased sCD14, which was postulated to contribute
to increased immune activation [104].
In HIV–HBV coinfection, it is possible that immune
activation might be increased by the synergistic effect
of both viruses, as recently demonstrated in HIV–
HCV coinfection [105]. Microbial translocation was
increased in individuals with HIV–HCV coinfection and
the presence of cirrhosis was related to levels of LPS,
LPS binding protein, sCD14, Aleuria aurantia lectin
and endotoxin core antibodies [105]. Similar data from
individuals with HIV–HBV coinfection are lacking.
Other factors
The initiation of HAART in individuals with HIV is
associated with significantly increased ALT levels in up
to 10% of cases [106], and higher rates might be seen
in individuals with HIV–HBV coinfection [72]. Possible
mechanisms for hepatotoxicity secondary to HAART
include cumulative dose-related liver injury with drugs
such as nevirapine [107], hypersensitivity reactions to
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Liver disease pathogenesis in HIV–HBV coinfection
nevirapine or abacavir [108] or mitochondrial damage
from drugs less commonly used now, such as didanosine,
zidovudine or stavudine [109]. Several protease inhibitors (including the recently licensed darunavir) and a new
non-nucleoside reverse transcriptase inhibitor, etravirine,
have also been associated with increased hepatotoxicity in
HIV–HBV-coinfected patients, although the mechanism
of this is not currently understood [110]. The new classes
of antiretrovirals, including the integrase inhibitor, raltegravir, and CCR5 antagonist, maraviroc, have not been
associated with enhanced hepatotoxicity in the setting
of HIV-hepatitis coinfection, although larger long-term
studies of these newer agents are required [111,112].
Cirrhosis has been reported in 1% of HIV-positive
individuals in the absence of coinfection with viral
hepatitis compared with approximately 6% in those
coinfected with HBV [113]. In addition, HIV monoinfection has been associated with portal hypertension
without the presence of advanced fibrosis, but with various histological findings, including nodular regenerative hyperplasia [114], microvesicular steatosis or perisinusoidal fibrosis. Prolonged use of HAART agents,
such as didanosine, might lead to mitochondrial toxicity or microvascular changes via portal endothelial cell
toxicity, resulting in these histological changes [114].
Mitochondrial toxicity might cause direct hepatocellular apoptosis or necrosis or indirect damage via reactive
oxygen species, lipid peroxidation and inflammatory
cytokines such as TNF-α, TGF-β and Fas ligand [115].
These processes are also important in steatohepatitis,
which might be present in HIV, either because of alcoholic or non-alcoholic steatohepatitis [115,116].
Conclusions
The explanation for increased liver-related mortality in
HIV–HBV coinfection compared with either infection
alone is likely to be complex, involving both viruses and
the immune response to each virus. HIV infects multiple
cells in the liver both in vivo and in vitro. Therefore, there
is an opportunity for HIV to alter the life-cycle of HBV,
although evidence to date is limited. Unique mutations in
HBV have been defined in HIV–HBV-coinfected individuals and might directly alter pathogenesis. In addition,
an impaired HBV-specific CD4+ or CD8+ T-cell immune
response in the setting of HIV is likely to be important.
The role of microbial translocation and immune activation, together with reduced NK cell activity and increased
hepatocyte apoptosis causing increased HSC activation,
will be important areas for future study.
Acknowledgements
DMI is a recipient of a postgraduate scholarship from
the National Health and Medical Research Council
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Lewin.indd 161
(NHMRC; Australia). SRL is an NHMRC practitioner
fellow and receives funding from the NHMRC, Alfred
Foundation (Australia) and National Institutes of
Health (1 R01 AI060449; USA).
Disclosure statement
The authors declare no competing interests.
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Accepted for publication 11 November 2008
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