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Departments of
*
Pathology and
Microbiology/Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
Departments of Neurology, Microbiology, and Immunology, University of Kentucky, Lexington, KY 40536; and
§
Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tat is required for efficient viral gene expression, interacting with
sequences in the HIV long terminal repeat to enhance transcription and
RNA processing (6). In addition to its effects upon viral
gene transcription, Tat is capable of modulating the expression of
several host genes. A proinflammatory role for Tat is indicated by its
ability to induce adhesion molecule and cytokine expression on
monocytes (7, 8) and endothelial cells (Refs. 9, 10 and our unpublished observations). In human astrocytes, HIV-1
Tat induces both NF-
B binding and protein kinase C activity
(11). It was recently demonstrated that Tat induces
monocyte chemoattractant protein (MCP)-1 expression in human astrocytes
(12). MCP-1 is a chemokine that potently recruits
monocytes as well as activated lymphocytes to areas of inflammation
(reviewed in Ref. 13). We and others have identified MCP-1
in the brains and cerebrospinal fluid (CSF) of patients with AIDS
encephalitis and AIDS dementia (Ref. 12 , C. M. McManus, K.
Weidenheim, and J. W. Berman, unpublished observations).
In addition to its intracellular effects, several studies have shown
that Tat can be secreted extracellularly by infected cells (14, 15). Furthermore, Tat has been detected in the serum of
HIV-1-infected individuals (15). In that study, the
concentration of Tat in the serum was 
1–3 ng/ml. Recently, we
demonstrated that Tat protein is present in HIV-1-infected human and
macaque monkey brains (16). Specifically, Tat is present
in close proximity to infected cells and neurons. It is therefore
important to examine the potential effects of the uptake of
extracellular Tat by resident glial cells. To obtain a more complete
understanding of the mechanisms whereby secreted HIV-1 Tat may modulate
leukocyte trafficking and, potentially, their susceptibility to
infection, we focused on the Tat-mediated modulation of chemokine and
chemokine receptor expression in human PBMC and in the cells that
constitute the BBB, namely, endothelial cells (ECs) and astrocytes.
We previously characterized a tissue culture model of the human BBB in
which astrocytes and ECs are cocultured on opposite sides of a porous
tissue culture insert (17). We demonstrated that direct
cell contact between EC and astrocytes through the pores of the insert
induces the expression of BBB markers, such as glucose transport
protein-1 (Glut-1) and 
-glutamyl-transpeptidase (gt), on EC. The
same coculture system was used by Hayashi et al. (18), who
also detected endothelial expression of Glut-1 and gt, as well as
barrier activity against inulin. We demonstrated previously that
cytokine-induced MCP-1 plays a central role in directing the
transmigration of monocytes and activated lymphocytes across these
cocultures (19). In those studies, leukocyte
transmigration in response to cytokines and MCP-1 was the same,
regardless of whether human umbilical vein or human brain microvascular
EC were cocultured in the model. Similarly, we showed that the adhesion
molecules that are critical for transmigration were identical,
regardless of the source of EC.
A role for chemokines in regulating the progression of HIV infection has also been identified by the ability of chemokine receptors to function as coreceptors that mediate HIV entry. Various HIV-1 isolates are capable of utilizing specific chemokine receptors, including CCR5, CCR3, CXCR4, and possibly CCR2, as coreceptors (20, 21, 22, 23). With the exception of CCR2, these receptors have been identified within the normal CNS on microglia and neurons (22, 24, 25). We and others detected CCR5, CXCR4, and CCR2-positive macrophages in the brains of those with pediatric HIV-1 encephalitis (24, 26).
In this study, we demonstrate that Tat induces monocyte transmigration that is mediated through astrocyte-derived MCP-1 expression. Furthermore, Tat up-regulates CCR5 expression on monocytes. Our data support a process whereby HIV-1 Tat protein contributes to HIV-1 infection of the CNS and the progression of AIDS dementia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study is part of an ongoing research protocol that has been approved by the Albert Einstein College of Medicine Committee on Clinical Investigation and the City of New York Health and Hospitals Corporation. Informed consent was obtained from all participants. Fetal tissues were obtained at the time of elective termination of intrauterine pregnancy from healthy females (27).
Cell culture
Astrocyte cultures were prepared according to a modified protocol of McCarthy and de Vellis (28). Briefly, human fetal CNS tissue was separated from the meninges, minced, and digested in 0.25% trypsin (Life Technologies, Grand Island, NY)/0.1% collagenase (Sigma, St. Louis, MO). The resulting cell suspension was serially filtered through sterile 100- and 80-µm nylon mesh filters (Tetko, Elmsford, NY) and pelleted at 900 rpm. Cultures were established in RPMI supplemented with 10% FCS and 1% penicillin/streptomycin (Life Technologies). After 12 days, microglial cells were removed from the mixed culture by shaking for 30 min at 4°C. Cultures were passaged after trypsinization and were examined by fluorescence microscopy for glial fibrillary acidic protein (IgG1; 1:50; Boehringer Mannheim, Indianapolis, IN), anti-macrophage as a marker for cells of the monocyte/microglia lineage (HAM56; IgM; 1:50; Enzo Diagnostics, Farmingdale, NY), and isotype-matched control Abs (IgG1 mouse myeloma; 1:50; Organon Teknika (Durham, NC), and anti-medullary and subcapsular cortical thymic EC; IgM; 1:50; Sigma Diagnostics, respectively). Astrocyte cultures (three to five passages) were >99% glial fibrillary acidic protein positive and unreactive for either HAM56 or control Abs. Thus, cells of the third or later passage were used to ensure the absence of contaminating microglial cells.
EC were obtained by digesting umbilical cords with type II collagenase (2 mg/ml, Worthington Biochemical, Freehold, NJ) and were grown on 0.2% gelatin (Fisher Scientific, Pittsburgh, PA)-coated tissue-culture plates in M199 medium (Life Technologies) supplemented with 20% newborn-calf serum (Life Technologies), 5% heat-inactivated human serum (Biocell Laboratories, Rancho Dominguez, CA), 1% penicillin/streptomycin, and 12 ng/ml EC growth factor (Sigma). Cultures were >99% factor VIII positive, as demonstrated by immunofluorescence using an anti-factor VIII-related Ag Ab (IgG1; 1:100; Dako, Carpinteria, CA) and unreactive for an isotype-matched negative control (IgG1 mouse myeloma protein; 1:50; Organon Teknika).
Establishment of EC and astrocyte cocultures
Cocultures of EC and astrocytes were established on opposite
sides of gelatin-coated, 3 µm pore-size tissue culture inserts
(Falcon, Becton Dickinson Labware, Franklin Lakes, NJ) as previously
described (17). This model exhibits EC expression of
Glut-1 and gt (17, 18) and barrier resistance to inulin
(18). Astrocytes (1 x 105
cells) were first seeded onto the underside of the insert. They were
allowed to attach for 4–5 h, after which the insert was placed upright
into a 24-well tissue culture plate containing complete M199 medium. EC
(1.6 x 104 cells) were applied to the
gelatin-coated inside of the insert. Cocultures were maintained for 3
days, after which inserts were transferred to new wells containing Tat
solution using M199 medium supplemented with only 10% newborn-calf
serum and no human serum. This medium was used throughout the
transmigration assay so as to minimize the effect of serum on MCP-1
expression (29). Cocultures were treated with 10 or 100
ng/ml Tat on the underside (astrocyte side) for 24 h.
Reagents
Recombinant Tat was prepared by expressing the tat
gene encoding amino acids 1–72 (first exon) as a fusion protein in
Escherichia coli DH5
F’IQ (Life Technologies). Tat was
purified as previously described (30) and diluted in the
following buffer before use: 50 mM Tris (pH 8.0), 100 mM NaCl, 1 mM
CaCl2, and 0.5 mM DTT. Endotoxin contamination of
Tat (at a concentration of 100 ng/ml) was determined to be <1.0 pg/ml
by Limulus amebocyte lysate assay (BioWhittaker,
Walkersville, MD). Tat was sterile filtered before treatments.
Recombinant human MCP-1 was purchased from Genzyme (Cambridge, MA). For
MCP-1 blocking experiments, the lower-chamber supernatants were removed
and preincubated with 10 µg/ml mAb 10F7 to MCP-1 (a generous gift of
Dr. Charles Mackay, formerly of Leukosite, Cambridge, MA) or IgG1 mouse
myeloma protein (Organon Teknika) as a negative control for 1 h.
The Ab to human CCR5 was from R&D Systems (Minneapolis, MN). Abs to
CCR2 and CXCR4 were a generous gift of Dr. Joseph Hesselgesser (Berlex
Biosciences, Richmond, CA).
Isolation of PBMC and PBMC transmigration
PBMC were isolated from freshly drawn human blood by Ficoll-Hypaque (Pharmacia Biotech, Piscataway, NJ) centrifugation as previously described (31). Briefly, whole blood was diluted 1:3 with PBS, layered over Ficoll-Hypaque (1:2.5), and centrifuged at 1400 rpm for 40 min at 18°C. The layer containing PBMC was removed and washed with cold PBS containing 1% FCS. Cells were spun at 1400 rpm for 20 min at 4°C, resuspended, and brought to a final concentration of 1.5 x 106 PBMC/ml. The tops of the inserts were washed with warmed medium. PBMC (3 x 105 cells in 200 µl) were added to the top of the insert, and inserts were examined microscopically for membrane integrity. For wells receiving MCP-1 as a positive control, 400 µl of MCP-1 at 100 ng/ml was added to the lower chamber. The transmigration assay was conducted for 2.5 h at 37°C.
Flow cytometric analysis
Transmigrated cells were collected from the lower-chamber supernatant. Cells adherent to the well bottoms were detached with 0.5 mM EDTA/PBS and pooled with the previously collected cells. Cells were spun at 300 x g and resuspended in a final volume of 400 µl of medium. CD45/CD14 Ab mixture (5 µl; Caltag Laboratories, Burlingame, CA) was added for a 30-min incubation at 4°C. This mixture contains FITC-conjugated anti-CD45, a panleukocyte marker, and PE-conjugated anti-CD14, a monocyte marker. Cells were spun, fixed in 2% paraformaldehyde, and analyzed within 12 h by flow cytometry.
Leukocyte transmigration was analyzed with a FACScan flow cytometer (Becton Dickinson Labware). The numbers of monocytes and lymphocytes per sample were determined by acquisition and analysis of list-mode data files using Lysis II software and the Consort 32 computer system. Gated acquisition was determined by a combination of gates based on forward and side scatters and CD45-FITC and CD14-PE reactivity. The starting populations of leukocytes and transmigrated samples were read for exactly 3 min.
For CCR5, CXCR4, and CCR2 expression on PBMC, 5–6 x 106 PBMC were plated in petri dishes and incubated with 1, 3, or 10 ng/ml of Tat for 4, 8, 24, or 48 h. Adherent cells were collected with 0.5 mM EDTA and brought to a final concentration of 1 x 106 cells/ml in 1% BSA/PBS containing mAb to CCR5, CXCR4, CCR2, or isotype-matched control Abs (5 µg/ml). Cells were incubated for 30 min at 4°C, washed, and incubated with FITC-conjugated goat anti-mouse IgG (Southern Biotechnology Associates, Birmingham, AL) for 30 min. Cells were fixed in 2% paraformaldehyde and analyzed for chemokine receptor expression by flow cytometry. Gated acquisition of monocytes (10,000 events) was performed based on forward- and side-scatter parameters.
ELISA
Culture supernatants were collected from the lower chamber and
stored at -20°C until use. MCP-1 protein was determined using a
sandwich-type immunoassay with capture and biotinylated detection Abs
(PharMingen, San Diego, CA). TNF- and IL-1ß were detected using
Abs purchased from R&D Systems. The minimum detection limit for these
assays is 15 pg/ml for MCP-1 and 5 pg/ml for TNF- and IL-1ß.
Statistical Analyses
Results from the duplicate wells of each transmigration experiment were averaged. Student’s paired t test was used to analyze significance of the numbers of transmigrated monocytes or MCP-1 protein in Tat-treated cultures, as compared with that of untreated cultures. For MCP-1 blocking experiments, significance between anti-MCP-1 and negative control Ab-treated supernatants was similarly compared. Results were considered to be significant for p < 0.05 values.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cocultures of EC and astrocytes were treated with 10 ng/ml HIV-1
Tat protein on the underside (astrocyte side) for 24 h. The
lower-chamber supernatant was analyzed by ELISA for MCP-1 expression.
Tat treatment of cocultures significantly induced MCP-1 expression, as
compared with untreated cocultures (Fig. 1
; p < 0.04;
n = 3). The addition of Tat to astrocytes cultured on
the inserts in the absence of EC resulted in similar amounts of MCP-1
protein (Fig. 1). In contrast, when EC cultured on the insert in the
absence of astrocytes were treated by addition of 10 ng/ml Tat to the
lower chamber, no induction of MCP-1 was observed (Fig. 1). These
findings demonstrate that Tat directly induced MCP-1 expression by
astrocytes. Significant levels of MCP-1 protein were detected using 100
ng/ml Tat as well, and there was no significant difference in the
amount induced (data not shown). Treatment of cocultures with Tat
diluent buffer alone in medium did not induce MCP-1 expression (data
not shown). To determine whether other cytokines were induced by Tat
treatment, we analyzed the culture supernatants for TNF- and IL-1ß
expression. Neither of these cytokines was induced by Tat treatment
(data not shown).
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, MIP-1ß, RANTES, and
inflammatory protein-10 expression. We also detected only 330 pg/ml
IL-8 protein in these supernatants. Thus, in our coculture model, MCP-1
appears to be the predominant monocyte chemoattractant induced by
Tat. Tat treatment of cocultures induces monocyte transmigration that is MCP-1 mediated
We determined whether Tat-induced MCP-1 expression in cocultures
induced leukocyte transmigration. Cocultures were treated with 10 ng/ml
Tat in the lower chamber (astrocyte side) for 24 h. Following Tat
treatment, the upper-chamber supernatant was removed, and PBMC were
added for the transmigration assay. As shown in Fig. 2, significant monocyte transmigration
was observed across Tat-treated cocultures, as compared with untreated
cultures (p < 0.04; n = 3). No
significant lymphocyte transmigration was detectable, as compared with
untreated cocultures (p > 0.10; data not
shown). As a positive control, the exogenous addition of 100 ng/ml
MCP-1 to the lower chamber induced equivalent monocyte transmigration
(p < 0.04; n = 3). Significant
monocyte transmigration was also detected using 100 ng/ml Tat (data not
shown). In contrast, no significant monocyte transmigration was
detected in the absence of astrocytes (EC cultured alone on inserts;
see Fig. 2). Again, as a positive control, the addition of 100 ng/ml
MCP-1 induced significant monocyte transmigration across EC
grown alone (Fig. 2). Treatment of cocultures with medium
containing Tat diluent buffer had no effect on monocyte transmigration
(data not shown).
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, Tat-induced monocyte transmigration
was completely inhibited by anti-MCP-1 pretreatment, as compared
with preincubation with an isotype-matched control Ab
(p < 0.03; n = 3). This was
observed for 100 ng/ml Tat as well (data not shown). As a control, the
MCP-1-mediated monocyte transmigration was also completely inhibited by
anti-MCP-1 treatment (Fig. 3). Thus, Tat-induced monocyte
transmigration is dependent on astrocyte-derived MCP-1 expression.
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In addition to mediating leukocyte recruitment, we hypothesized that Tat may alter the expression of chemokine receptors on PBMC. To test this, freshly isolated PBMC were incubated with increasing doses of Tat protein (1, 3, or 10 ng/ml Tat) for various lengths of time (4, 8, 24, or 48 h). These concentrations of Tat are similar to those detected in the sera of HIV-1-infected individuals and the supernatants of HIV-1-infected cell cultures (15). PBMC were then collected and analyzed for chemokine receptor expression by flow cytometry. Monocytes were gated according to forward- and side-scatter parameters. For all treatment conditions, similar results were obtained from more than one donor.
Fig. 4A illustrates the
expression of CCR5, as determined by mean fluorescence intensity, by
untreated monocytes as compared with those treated with Tat. After 24
or 48 h of Tat treatment, the expression of CCR5 on monocytes was
greater than that of the corresponding cultures that did not receive
Tat (untreated). At these later time points, enhanced CCR5 expression
was observed for all doses of Tat, which reached significance for 3 or
10 ng/ml Tat at 24 h and for 3 ng/ml Tat at 48 h
(p < 0.02 each; n = 2). No
change in CCR5 expression was detected at either 4 or 8 h of Tat
treatment, regardless of the dose of Tat (Fig. 4A). For each
treatment condition, PBMC cultures were also incubated with an
isotype-matched mouse myeloma protein as a negative control. The
staining intensities for this negative control remained unaffected by
the addition of Tat (data not shown). The expression of CCR5
in the untreated cultures was unchanged over 48 h in culture
(Fig. 4A).
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, B–D, further illustrate the
increase in CCR5 expression detected for 10 ng/ml Tat at 24 h. As
shown in Fig. 4B, untreated monocytes (plated for 24 h)
had a low level of CCR5 expression, as compared with the negative
control Ab staining. Treatment of PBMC with 10 ng/ml Tat for 24 h
increased CCR5 expression (Fig. 4C; n = 5)
while having no effect on control Ab staining (Fig. 4D).
We next analyzed CXCR4 expression on PBMC, because this receptor serves
as a coreceptor for efficient entry of syncytium-inducing strains of
HIV-1 (20). Untreated monocytes were found to express
CXCR4 (Fig. 5A;
n = 4). However, the expression of CXCR4 remained
unaltered after 24 h of Tat treatment (Fig. 5B; 10
ng/ml Tat).
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C;
n = 4); however, Tat treatment (10 ng/ml for 24 h)
did not significantly modulate this expression (Fig. 5D). The effect of Tat on PBMC chemokine receptor expression thus appears to be specific for CCR5 at the time points tested.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, multiple pathways are likely to exist
for this process. They include the following: 1) Tat may induce
monocyte transmigration across the BBB through astrocyte-derived MCP-1
expression (Fig. 6A); 2) HIV-1 Tat may also directly induce
monocyte transmigration (Fig. 6B); 3) Tat may activate
monocytes and microglia for enhanced cytokine (e.g., TNF- and
IL-1ß) and chemokine production, including MIP-1, MIP-1ß, and
RANTES (Fig. 6C); and 4) Tat up-regulates CCR5 expression on
monocytes, which may facilitate their migratory response to these
chemokines as well as their infectivity (Fig. 6D)
(21).
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, nitric oxide, platelet-activating
factor, or arachidonic acid metabolites that may directly contribute to
neuronal injury and/or death (34). Lafrenie et al. (35) found that HIV-1 Tat directly induced monocyte transmigration across Matrigel-coated inserts without any cells grown on it. This was particularly evident when the monocytes were pretreated with HIV-1 Tat. Tat may therefore directly facilitate the transmigration of monocytes across the BBB.
HIV encephalitis is often associated with elevated levels of
proinflammatory cytokines in the CNS (36). Astrocytes are
a potential source of TNF- (37, 38), and both EC and
astrocytes can produce IL-1ß (39). We examined whether
Tat induced either TNF- or IL-1ß production in our cell cultures,
because these cytokines can also induce MCP-1 expression. However, by
ELISA we did not detect the expression of either cytokine in
Tat-treated EC, astrocytes, and cocultures. This is consistent with
previous observations that Tat, at 10 ng/ml (714 pM), was unable to
induce TNF- production in astrocytes (40).
Specifically, in that study, at least 1 µM Tat was necessary to
induce the production of TNF- from human fetal astrocytes. Tat has
been shown to be a potent stimulus of TNF- in macrophages; however,
at least 10 nM Tat for 4 h was required for this effect
(40). Thus, our findings rule out the possibility that
TNF- is involved in Tat-induced MCP-1 expression in our cocultures.
This is not surprising, given that we treated cells with Tat at a
concentration that does not induce TNF- expression in astrocytes
(40). Furthermore, any potential TNF--induced MCP-1
expression is also not a mechanism in our studies, given that Peterson
et al. (41) have shown that at least 20 ng/ml TNF- is
required to induce MCP-1 expression in astrocytes and that we did not
detect any TNF- in our Tat-treated cultures. These observations
suggest an important and direct role for Tat-induced MCP-1 production
by astrocytes in the transmigration of monocytes.
We demonstrate that HIV-1 Tat up-regulates CCR5 receptor expression on
human peripheral blood monocytes. This effect was observed using as
little as 1–3 ng/ml Tat, doses that are similar to the levels of Tat
that have been found in the sera of HIV-infected patients (15, 16). We further show that at least 24 h of Tat treatment
was required for the induction of CCR5 expression. Our findings
complement those of Huang et al. (42), who recently
reported that Tat induces CCR5, as well as CXCR4 and CCR3 expression on
monocytes. In that study, PBMC were incubated with 100 ng/ml Tat for at
least 2–8 days. Taken together, our data and theirs demonstrate that
the effects of Tat on chemokine receptor expression in PBMC occur as
early as 24 h and persist for at least 8 days. Furthermore, our
own finding, that Tat, at lower concentrations and earlier times,
increases CCR5 expression but not that of CXCR4, suggests that the
induction of these chemokine receptors by Tat is mediated through
distinct pathways. The up-regulation of CCR5 expression by Tat is an
interesting observation, because studies suggest that proinflammatory
cytokines such as TNF- may decrease CCR5 expression
(43). The ligands for CCR5, specifically MIP-1 and
MIP-1ß, have also been detected in AIDS encephalitis
(44). We demonstrated that human microglia
(45), as well as Tat-treated astrocytes (26),
are potential sources of these chemokines. Thus, in addition to MCP-1,
it is possible that MIP-1 or MIP-1ß participates in Tat-mediated
leukocyte transmigration across the BBB in vivo. However, MCP-1 was
demonstrated in chemotaxis assays across EC to be the most potent of
these monocyte chemoattractants (46). Our finding that Tat
up-regulates CCR5 expression on monocytes may have important
implications in vivo for CCR5-mediated chemoattraction and/or infection
of monocytes.
CCR5 is a coreceptor that mediates fusion and entry of M-tropic strains
of HIV (21). Its up-regulation may therefore indicate a
process whereby HIV facilitates its own replication. However, the
chemokines MIP-1, MIP-1ß, and RANTES are capable of binding to
this receptor and suppressing HIV infection (47). Thus,
the overall balance of chemokine and virus concentrations is likely to
determine the susceptibility of CCR5+ cells to
infection.
We demonstrate that HIV-1 Tat facilitates the transmigration of monocytes via astrocyte-derived MCP-1 expression. We further show that Tat up-regulates the expression of CCR5 on human monocytes. Our findings indicate important mechanisms whereby HIV-1 Tat may not only facilitate the entry of infected and/or uninfected monocytes into the CNS, but also may render monocytes more susceptible to HIV-1 infection, thereby contributing to the pathogenesis of AIDS dementia.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joan W. Berman, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461. E-mail address:
3 Abbreviations used in this paper: BBB, blood-brain barrier; CSF, cerebrospinal fluid; MCP-1, monocyte chemoattractant protein-1; EC, endothelial cells; Glut-1, glucose transport protein-1; gt, -glutamyl-transpeptidase; MIP, macrophage-inflammatory protein.
Received for publication December 16, 1998. Accepted for publication June 25, 1999.
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E. A. Eugenin, K. Osiecki, L. Lopez, H. Goldstein, T. M. Calderon, and J. W. Berman CCL2/Monocyte Chemoattractant Protein-1 Mediates Enhanced Transmigration of Human Immunodeficiency Virus (HIV)-Infected Leukocytes across the Blood-Brain Barrier: A Potential Mechanism of HIV-CNS Invasion and NeuroAIDS J. Neurosci., January 25, 2006; 26(4): 1098 - 1106. [Abstract] [Full Text] [PDF]
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R. L. Caldwell, R. Gadipatti, K. B. Lane, and V. L. Shepherd HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells J. Leukoc. Biol., January 1, 2006; 79(1): 192 - 201. [Abstract] [Full Text] [PDF]
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