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HIV-1 infection in macrophages and genes involved throughout: Big eaters versus
small invaders
Cobos Jiménez, Viviana
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Cobos Jiménez, V. (2014). HIV-1 infection in macrophages and genes involved throughout: Big eaters versus
small invaders
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GENERAL INTRODUCTION
Partly adapted from:
Viviana Cobos Jiménez, Thijs Booiman, Jörg Hamann and Neeltje A. Kootstra.
Macrophages and HIV-1. 2011. Curr. Opin. HIV. AIDS. 6;(5): 385-390.
And
Sebastiaan M. Bol, Viviana Cobos Jiménez, Neeltje A. Kootstra
and Angelique B. van ‘t Wout. HIV-1 and the Macrophage. 2011.
Future Virology. 6;(2): 187-208.
GENERAL INTRODUCTION
MONOCYTES AND MACROPHAGES
Macrophages are effector cells of the innate immune response, and are responsible
for sensing and clearing pathogens, thus playing an important role in establishing
primary as well as adaptive immune responses. These cells also contribute to
regulation of tissue homeostasis, inflammation and repair1. Derived from a
common myeloid progenitor, monocytes that originate in the bone marrow are
released into the blood stream. Monocytes subsequently migrate to the tissues,
where they mature into macrophages and can encounter a number of stimuli that
can shape their physiology (Figure 1). Cytokines that are produced by either innate
or adaptive immune cells are responsible for skewing macrophages into two main
phenotypic subpopulations: M1 or M2, with M1 macrophages typically producing
high levels of IL-12 and low levels of IL-10, and M2 macrophages producing
high levels of IL-10 and low levels of IL-12. M1 macrophages are generated by
stimulation with IFN-γ and TNF-α or LPS, and have pro-inflammatory profile.
These classically activated macrophages are characterized by high production of
pro-inflammatory cytokines (IL-1, IL-6, IL-12, and TNF-α) and a high microbicidal
activity2. M2 or alternatively activated macrophages comprise a broad variety of
cells with different characteristics. However, they are all mediators of Th2 or antiinflammatory responses and may be involved in tumorogenesis. M2 macrophages
can be divided in three main groups: M2a, M2b and M2c. M2a macrophages are
induced by exposure to IL-4 or IL-13, produce high levels of anti-inflammatory
cytokines IL-10 and IL-1ra (receptor antagonist), and are involved in wound
healing, tissue repair and, in some cases, killing and encapsulation of parasites3,4.
They are also involved in allergic responses and recruit other immune cells to
inflammation sites1. M2b macrophages are primed by stimulation with IgG
immune complexes and are further activated by TLR ligands. These cells produce
proinflammatory cytokines (IL-1, IL-6, TNF-α), but in contrast to M1 macrophages
they also produce IL-10. This subpopulation of activated macrophages plays an
important role in mediating anti-inflammatory responses, and development of
humoral responses. In these macrophages, binding of the FcγR to an antigenIgG complex will elicit IL-10 production, which will prompt T cells to produce
IL-4, thus stimulating B cells to produce antibodies against such antigen2. M2c
macrophages are generated by stimulation with IL-10 or glucocorticoids, are
involved in immune suppression and regulation of inflammation, and produce
IL-10 and TGF-β3,4 (Figure 1). It has been proposed that the activation process
of macrophages occurs in a successive manner, instead of being a single-step
stimulation event, and goes from initial priming, full activation into effector cells
and subsequent deactivation by anti-inflammatory mediators5.
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Figure 1. Schematic representation HIV-1 susceptibility of macrophages during maturation and
polarization. Circulating monocytes (A) can migrate to several tissues and mature into macrophages
(B). In these tissues, these cells are exposed to different stimuli that allow their polarization into
specific subpopulations: M1 macrophages (C) or M2 macrophages (D). Polarized macrophages
can be characterized by their immune functions and production of cytokines. During maturation
and activation, the various populations differ in their susceptibility to HIV-1 infection (E).
MACROPHAGES AND THE HUMAN IMMUNODEFICIENCY
VIRUS TYPE 1 (HIV-1)
Macrophages are important target cells for HIV-1, and due to their ubiquitous
distribution and their capacity to migrate to other tissues, they contribute greatly
to the spread of the viral infection to CD4+ T cells and the establishment of the
viral reservoir. Although the introduction of combined antiretroviral therapy
(cART) has contributed to the control of viral load in infected patients, residual
viremia can still be detected when using highly sensitive methods6. Macrophages
are long lived cells that are resistant to the cytopathic effects of viral infection7.
Additionally, HIV-1 induces anti-apoptotic mechanisms in macrophages that allow
for continuous production viral particles for long periods of time8,9. Poor tissue
penetration of antiretroviral drugs prevents inhibition of viral replication in these
cells, allowing them to reside in sanctuary sites, such as the testis10, gut associated
lymphoid tissue11, the brain12 and the bone marrow13.
Furthermore, it has been shown that HIV-1 infected macrophages render
resting T cells permissive for infection14,15, which indicates that both the resting
T cell and the macrophage reservoirs are connected. Viral reservoirs such as
macrophages contribute to the development of HIV-1 associated diseases and
make eradication of the virus from the host a challenging task.
GENERAL INTRODUCTION
ROLE OF MACROPHAGES IN TRANSMISSION OF HIV-1
Macrophages are of great importance in the spread of the virus from host-tohost, during mucosal transmission, and are also central players during cellular
transmission of HIV-1 from cell-to-cell.
Host-to-host transmission
HIV-1 transmission occurs mainly through mucosal tissue after translocation of the
virus across the epithelium. Since macrophages constitute the largest population
of immune cells in the subepithelial lamina propria, it is thought that macrophages
play a role in transmission of the virus from host-to-host16. Organ culture systems
derived from cervical tissue allowed for the identification of CD4+ T cells as the
first cells being infected after contact with cell-free CCR5-using HIV-1, but also
helped to identify Langerhans cells and macrophages as early target cells for HIV-1
infection17. In addition, macrophages were found to be present in the mucosa
and submucosa of human vagina and foreskin, which are also early sites of HIV-1
replication before the virus disseminates18,19. Finally, the predominant infection of
macrophages by CCR5-using HIV-1 may be one of the factors contributing to the
predominant transmission of these variants from host-to-host20,21.
Cell-to-cell transmission
Transmission of HIV-1 can occur from infected macrophages to CD4+ T cells upon
cell-to-cell contact and it is accompanied by activation of the T cells. Cell-to-cell
transmission is more efficient than infection by cell-free virus22. The virological
synapse, the structure between the infected cell and an uninfected permissive
target cell, is used for the transfer of HIV-123. In macrophages, HIV-1 induces
the formation of tunnelling nanotubes which the virus uses for transfer to the
connected cell24. In addition, macrophages and microglia express mannosereceptors that can bind and endocytose HIV-1, allowing subsequent transmission
to CD4+ T cells without infection of the macrophage25. Expression of DC-SIGN
plays a role in the transmission of HIV-1 from macrophages in colostrum (early
breast milk) to recipient cells in the new born child26,27.
CELLULAR FACTORS INVOLVED IN HIV-1 REPLICATION
IN MACROPHAGES
Monocytes are refractory to HIV-1 infection in vitro, yet become susceptible to
infection during differentiation into macrophages28,29. For efficient replication,
HIV-1 continuously interacts with the cellular machinery of macrophages, and
several studies have identified cell type-specific factors, including miRNAs, that
are involved at different steps of the replication cycle of the virus.
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Monocytes
Although freshly isolated monocytes express reasonably high levels of CD430,
expression of CCR5 is low31,32. Still, HIV-1 is able to efficiently enter the cells,
however the process of reverse transcription is not completed28,29 probably due
to the low levels of dNTP in non-dividing cells33,34. A 32 base pair deletion in the
gene encoding for CCR5 influences macrophage susceptibility to HIV-1; donors
with a heterozygous genotype (CCR5 wt/Δ32) are less permissive to infection35,36,
whereas the absence of CCR5 on the cell surface (CCR5 Δ32/Δ32) results in
complete resistance to infection with a CCR5-using virus36,37.
Monocyte-derived macrophages
HIV-1 susceptibility of macrophages in vitro is enhanced by growth factors like
M-CSF or GM-CSF38-40. The increase in susceptibility of macrophages to HIV-1
infection during differentiation correlates with enhanced CCR5 expression31,32,41.
Despite expression of CXCR4 on macrophages, these cells are refractory to
infection with most CXCR4-using HIV-1 isolates in vitro42, perhaps because of
lack of an association between CXCR4 and CD4 on the cellular membran43.
Furthermore, additional to binding to the co-receptor, the subsequent intracellular
signalling also influences the ability of HIV-1 to replicate in macrophages44.
The ability of primary macrophages to support HIV-1 replication in vitro was found
to be highly variable and dependent on the donor, suggesting that genetic variations
may contribute to susceptibility to HIV-1 infection36. A genome-wide association
study identifying genetic polymorphisms allowed identification of factors like PDE8A
and DYRK1A that play a role in HIV-1 susceptibility of primary macrophages45,46.
During the replication cycle, HIV-1 utilizes the cellular machinery of macrophages
in order to produce new viral progeny. Differential expression of cellular factors
during macrophage differentiation, activation and polarization might explain
changes in susceptibility of these cells to HIV-1 infection, despite the variation
between individuals. Several studies have identified cellular proteins that interact
with HIV-1 at different steps in the replication cycle in primary macrophages.
HIV-1 infects macrophages through binding of the HIV-1 envelope protein gp120
to CD4 and CCR5, followed by viral uptake and entry into the cell. Other cellular
factors that contribute to viral entry are the integrin αvβ547 and a novel endocytic
entry pathway, which is dependent on actin rearrangements, Na+/H+ exchange,
Rac GTPase, N-WASP, Pak1, and dynamin GTPase48.
In the cytoplasm, the viral RNA is reverse transcribed into a double-stranded
DNA genome. In macrophages, reverse transcription and subsequent integration
were restricted by Trim5α49, Cyclophilin A50 and APOBEC3G51,52. In contrast, CD63,
supports reverse transcription and subsequent steps of the viral replication cycle53.
Furthermore, nuclear translocation and integration of the viral genome
requires phosphorylation of the emerin protein by virion-associated ERK/MAPK in
GENERAL INTRODUCTION
non-dividing cells54. NAMPT is able to decrease the levels of integrated proviral
DNA in MDM55. After integration, the viral genome is transcribed by the cellular
machinery, leading to protein production and assembly of new viral particles. Early
in infection mainly non-full length HIV-1 transcripts are generated, resulting in the
translation of the HIV-1 protein Tat. HIV-1 Tat recruits the host proteins CyclinT1, NL-IL6 and CDK9 to form a complex that binds the HIV-1 LTR and enhances
elongation of HIV-1 transcripts56,57. However, the small isoform of the C/EBPβ gene
is a dominant negative transcription factor that blocks viral DNA transcription58-60.
Trim22 and OTK18 (ZNF175) can also suppress HIV-1 LTR promoter activity61,62. In
microglia, the DNA repair protein Rad51 enhances NF-κB-induced transcription63.
Late in the viral replication cycle, TIP47 is essential for the production of
infectious new viral particles and Anexin2 maintains infectivity of the viral progeny
in infected primary macrophages64,65. Tetherin (BST2) and Alix (AIP1) block viral
release from the cellular membrane of macrophages66,67.
Role of microRNAs in HIV-1 infected macrophages
Cellular microRNA (miRNA) pathways have been described to interfere with HIV-1
replication and contribute to viral latency by targeting HIV-1 transcripts or cellular
RNAs encoding for proteins essential for replication. Expression of cyclin T1 can
be regulated by miR-198, abundantly expressed in monocytes, and therefore
regulates Tat-dependent gene expression68.
Expression of a number of cellular miRNAs that directly target HIV transcripts
(miR-28, miR-150, miR-223, and miR-382), decreases during differentiation of
monocytes into macrophages69 and it is inversely correlated with the susceptibility
to HIV-1 infection70.
HIV-1 can modulate the host RNA interference pathways to promote either
viral latency or suppress the innate responses against viruses. The HIV-1-accessory
proteins Vpr and, to a lesser extent, Nef down-regulated DICER expression, thus
suppressing the complete miRNA pathway in PMA- or M-CSF-treated macrophages
derived from U937 cells71. In microglial cells, the resident macrophages in the
Central Nervous System (CNS), HIV-1 induced expression of miRNA-146a, which
targets MCP-2, a potent inhibitor of CD4/CCR5-mediated HIV-1 entry63.
HIV-1 INFECTION OF POLARIZED MACROPHAGES
Several studies have reported the effects of cytokine stimulation on HIV-1 infection
of macrophages and determined that HIV-1 is inhibited in M1 or M2 polarized
macrophages72-75.
M1 Macrophages
HIV-1 inhibition has been attributed to low expression of CD4 and up regulation of
CCR5 binding chemokines and also inhibition of early (in M1) or late (M2) steps of the
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replication cycle72,76,77. Additionally, IFN-γ treatment alone also blocks HIV-1 replication
in macrophages and in most studies a decrease in proviral DNA is observed78-80.
Other proinflammatory cytokines produced by M1 activated macrophages may also
modulate HIV-1 infections in these cells. Studies have shown that HIV-1 replication
is inhibited at an early step by IL-681 and IL-1282, but is enhanced by CXCL1083 and
CCL284, at early and late steps in the replication cycle, respectively.
M2 Macrophages
In M2a macrophages, a more sustained inhibitory effect at a late stage in the
virus life cycle is observed72. Treatment of HIV-1 infected monocyte-derived
macrophages (MDM) with IL-4 alone stimulates HIV-1 reverse transcription, p24
production, and HIV-1 transcription by accelerating nuclear import of NF-κB85-88.
However, treatment of MDM prior to viral inoculation significantly reduces reverse
transcription and p24 production40,89-91, and is associated with the reduced
proliferative capacity, advanced maturation state90. Treatment with IL-13 also
inhibits HIV-1 replication, similar to IL-440,91.
HIV-1 replication in M2b macrophages generated using human IgG to crosslink FcγRs, either before or after viral inoculation, is strongly inhibited at the level of
proviral integration into the host genome74,75. Reversed transcription is also restricted
in these macrophages by the cyclin-dependent kinase inhibitor p21-Cip1/Waf 92.
Induction of M2c macrophages by IL-10 results in inhibition of viral replication
at a late step during infection, probably at the level of viral assembly93,94. However,
others show treatment of infected monocyte-derived macrophages with IL-10
and TNF-α increases HIV-1 replication, probably due to a synergistic effect95.
Additionally, IL-10 induces proteosomal degradation of Cyclin-T1, which in turn
has a suppressive effect on HIV-1 replication in macrophages96.
INNATE IMMUNITY TO HIV-1 AND EVASION STRATEGIES
OF THE VIRUS
Recent studies revealed contrasting roles for Toll-like receptor (TLR) ligands,
derived from different microbial invaders, in either suppressing or enhancing
HIV-1 replication in macrophages. Activation of TLR3, TLR4 and TLR9 leads
to inhibition of HIV-1 replication mostly by stimulation with type I intereferon
responses and other proinflammatory mediators97-100. However TLR5 activation
has been associated with enhanced virus production, and TLR8 stimulation
activates HIV from latently infected monocytic cell lines101,102.
Upon viral infection, receptors that recognize viral nucleic acids initiate a cellular
innate immune response. Central to this response are type I IFNs that potently inhibit
the early stage of HIV-1 replication103,104. Notably, HIV-1 infection in macrophages
neither triggeres NF-κB nor IRF3 pathways nor does it induce type I IFN gene
GENERAL INTRODUCTION
expression105. The molecular basis behind the lack of functional recognition of HIV-1
in macrophages is not completely understood. TREX1 might be one of the cellular
factors responsible for impeding type I IFN responses. This DNase binds to HIV-1
DNA copies in the cytoplasm, and digests excess of proviral DNA106. Additionally,
the phosphohydrolase SAMHD1 is capable to restricting reverse transcription of
HIV-1 in myeloid cells, by limiting the pool of nucleotides available to viral cDNA
synthesis107-109. Together, TREX1 and SAMHD1 prevent viral DNA to be abundant
in the cytoplasm, making it invisible to cytoplasmic DNA sensors that otherwise are
capable of triggering an innate antiviral response through IFN-β production, thus
enabling HIV-1 to escape this antiviral responses and be transmitted to T cells110.
In spite of the muted changes to the macrophage transcriptome upon HIV-1
infection105, different effects of HIV-1 have been reported. The HIV-1 accessory
protein Nef was shown to induce MIP-1α and MIP-1β production in macrophages,
thereby enhancing viral replication and dissemination by recruitment of T cells111.
HIV-1-infected monocytes and macrophages exhibit upregulation of programmed
death-1 (PD-1) and its ligands PD-L1 and PD-L2112,113. When engaged in combination
with the T-cell receptor, PD-1/ligand signaling results in an inhibitory signal affecting
proliferation and cytokine production, T-cell activation and recognition of the
infected macrophage. HIV-1 infection also impairs the ability of macrophages to
phagocytose pathogens opsonized by antibodies or complement114.
During HIV-1 replication in macrophages, Nef induces formation of
autophagosomes, although it inhibits their maturation in order to protect the
virus from degradation and limit presentation of viral peptides by MHC115. HIV-1
also inhibits autophagy activity of uninfected bystander cells in adjacent cells
through Src-Akt and STAT3 activation116 and inhibition of IFNγ-induced STAT1
phosphorylation117. Disruption of autophagy by HIV-1 interferes with the host
defense mechanisms against invading pathogens, thereby creating a favorable
environment for opportunistic infections.
In conclusion, HIV-1 does not evoke a strong innate immune response, involving
for instance type I IFN and NF-κB, upon infection of primary macrophages.
Although HIV-1-infected macrophages are dysfunctional, they are able to evade
recognition by the immune system and serve as viral reservoir, disseminating the
virus to various tissues.
PATHOLOGIES ASSOCIATED WITH HIV-1 INFECTION
IN MACROPHAGES
HIV-1-infected macrophages are involved in the development of different
pathologies, like AIDS-related lymphomas, cardiovascular diseases, and HIV-1associated neurocognitive disorders (HAND), of which HIV-1-associated dementia
(HAD) is the most severe complication118.
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Neurocognitive disorders
Early in the course of infection, HIV-1 transits to the CNS via infected macrophages
and lymphocytes where it settles in perivascular macrophages, microglia, and
astrocytes119-121. Although astrocytes are not productively infected, they form the
majority of cells in the brain and are critical for maintaining essential brain functions.
Production of proinflammatory chemokines, like CCL2, by infected macrophages,
microglia, and astrocytes increases transmigration of circulating infected monocytes
and macrophages over the blood-brain barrier (BBB)122. Once infected, the CNS
acts as a viral reservoir and is capable of re-seeding the periphery with HIV-1, most
likely via the meninges as primary transport tissue123. Replication in macrophages
and activated microglia leads to production of viral and proinflammatory proteins
creating a neurotoxic environment. Viral proteins, such as gp120, gp41, and Tat,
have strong neurotoxic effects and have been implicated in the development of
HAD124. HIV-1 Tat has a direct toxic effect on neurons and can induce expression
of adhesion molecules and chemokines in astrocytes and microglia attracting
monocytes/macrophages to the brain125. Tat also induces suppressor of cytokine
signaling 3 (SOCS3), thereby inhibiting IFN-β signaling, thus enhancing viral
replication in macrophages and promoting HAD development126.
Treatment of HIV-1-infected individuals with combined antiretroviral therapy
(cART) has diminished the prevalence of severe AIDS-related complications, like
HAD. However, milder forms of HAND are increasingly recognized in a substantial
number of aging HIV-1-infected individuals on cART and are now one of the most
feared complications of the infection118,127.
AIDS related lymphomas
Macrophages might also indirectly contribute to the onset of AIDS related cancers.
The occurrence of non-Hodgkin lymphomas in HIV-1 infected patients has decreased
since cART, but is thought to remain too frequent to only be associated with poor
immunity caused by the virus128,129. Excessive cytokine production by macrophages
could result in overstimulation of B cells with subsequent DNA modifications,
resulting in malignancy130,131. Cell-to-cell transmission from infected macrophages
to B cell through tunnelling nanotubes may contribute to the formation of AIDSrelated lymphomas (ARL)132,133. HIV-1 has not been found in malignant B cells, but
was present in tumor associated macrophages in the stroma128,134. Additionally, 40%
of the ARL tissues were found to harbour HIV-1 infected macrophages135.
Cardiovascular disease
HIV-1 infected patients have a greater risk to develop cardiovascular disease,
independent of the use of cART or of dyslipidemia136-139. Multiple studies have shown
that there is a direct effect of HIV-1 on plasma lipid levels, resulting in an atherogenic
lipoprotein profile136,140,141. HIV-1 induces systemic inflammation and expression of
GENERAL INTRODUCTION
cytokines, which recruits monocytes and macrophages to the damaged arterial wall,
promoting local differentiation and activation of the macrophages. This results in
increased uptake of lipids by macrophages, leading to the formation of foam cells
and of plaque at the inner lining of the inflamed artery142. In addition, expression of
the viral protein Nef in infected macrophages leads to higher production, uptake
and accumulation of cholesterol143-146. Therefore, through the increased cytokine
production and recruitment of infected monocytes and macrophages, HIV-1 may
contribute to the development of cardiovascular diseases143,146,147.
CONCLUSION
HIV-1 interacts with numerous cellular factors expressed in macrophages, during
the viral replication cycle. The effect of such cellular factors can be beneficial as
well as detrimental for viral replication, yet HIV-1 is capable to efficiently infect
macrophages and at the same time avoid triggering of immune responses that may
eliminate the virus or the infected cells. Due to this efficient evasion from immunity,
and wide tissue dissemination, virus-infected macrophages function as cellular
reservoir for the virus, becoming the main hurdle for the eradication of HIV-1.
It is still unclear how HIV-1 replication in macrophages is regulated, especially
upon cytokine polarization, and which mechanisms and cellular factors are involved.
It is of great importance to identify these factors in the macrophages, present at the
moment of infection, in non-activated as well as polarized/activated macrophages,
to reveal the exact mechanism of HIV-1 infection in these cells. Identification of
cellular factors involved in HIV-1 replication in macrophages will increase the
understanding of both virus- and cell-type-specific aspects of viral replication and
may identify new therapeutic alternatives that specifically target HIV-1 reservoirs.
SCOPE OF THIS THESIS
In this thesis we have studied the infectious process of HIV-1 in differently polarized
macrophages. The purpose of this research was to identify cellular factors that
are involved in HIV-1 infection of macrophages, how these factors affect viral
replication and whether their function or expression is affected by stimulatory
signals that macrophages encounter during their differentiation in the tissues.
In order to better understand the process of macrophage polarization, in
chapter 2, we have characterized expression of miRNAs in cytokine-polarized
macrophages, and identified specific miRNA expression signatures that are
associated with the macrophage physiology. In chapter 3, we have demonstrated
that HIV-1 infection is inhibited in M1 and M2 polarized macrophages. Analyses
of expression of cellular factors known to interact with HIV-1 during infection
indicated that the known factors are not associated with HIV-1 inhibition in M1 and
M2 macrophages. These data suggested that novel cellular factors are involved,
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and in chapter 4, we have indeed identified a novel HIV-1 restriction factor
expressed in macrophages and T cells, through the analysis of gene expression
profiles in M1 and M2 macrophages. We found that the GTPase Binding Protein
(SH3 domain) Binding Protein 1 (G3BP1) restricts HIV-1 replication by binding
to HIV-1 RNA transcripts, which delays mRNA translation and viral protein
production, therefore reducing production of new viral particles. In chapter 5
we have investigated the role of a recently described cellular factor PDE8A, in
HIV-1 replication in macrophages. We have identified the mechanism of HIV-1
restriction by PDE8A and show that PDE8A expression is regulated by cellular
miRNAs during maturation of monocytes into macrophages. In chapter 6 we have
analyzed how HIV-1 influences gene expression in macrophages upon infection,
and how this relates to gene expression in macrophage polarization by cytokines.
The findings of this work and its implications are discussed in chapter 7.
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