(Journal of Leukocyte Biology. 2000;68:360-365.)
© 2000
by Society for Leukocyte Biology
Biological parameters of HIV-1 infection in primary intestinal lymphocytes and macrophages
Phillip D. Smith*,
,
Gang Meng*,
Marty T. Sellers
,
Tina S. Rogers
and
George M. Shaw||
Departments of Medicine (
* Gastroenterology and
Rheumatology) and Surgery (
Transplantation), University of Alabama at Birmingham;
Birmingham Veterans Affairs Medical Center and the
|| Howard Hughes Medical Institute, Birmingham
Correspondence: Phillip D. Smith, M.D., Department of Medicine (Gastroenterology and Hepatology), UAB, 703 19th Street South, Birmingham, AL 35294.
 |
ABSTRACT
|
|---|
Mucosal surfaces are the portal of entry for most HIV-1 infections and
play an important role in disease pathogenesis. To characterize the
biological parameters of HIV-1 infection in mucosal cells, we used
purified lamina propria lymphocytes and macrophages from normal human
small intestine to determine the distribution of the HIV-1 receptor and
coreceptors on intestinal mononuclear cells and the permissiveness of
these cells to HIV-1 infection. Lamina propria lymphocytes expressed
CD4, CCR5, and CXCR4. In contrast, lamina propria macrophages expressed
CD4 but not CCR5 or CXCR4. Intestinal lymphocytes supported replication
by R5 and X4 isolates of HIV-1, but lamina propria macrophages were
permissive to neither. RANTES, macrophage inflammatory protein-1
(MIP-1), and MIP-1ß inhibited infection of intestinal lymphocytes
by BaL, indicating that R5 infection of the intestinal lymphocytes was
mediated by CCR5. Thus, resident lamina propria lymphocytes, not
macrophages, are the target mononuclear cell for HIV-1 infection in the
intestinal mucosa during early HIV-1 infection.
Key Words: mucosa • lamina propria • CCR5 • CXCR4
|
INTRODUCTION
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|---|
Mucosal surfaces play a fundamental role in the pathogenesis
of HIV-1 disease [1
]. First, the gastrointestinal tract
mucosa is the body surface through which HIV-1 enters the host in
homosexual and vertical transmission. During vertical transmission, the
upper gastrointestinal tract mucosa is particularly important,
providing the site of virus translocation after the fetus or infant
swallows HIV-1-infected amniotic fluid in utero, infected
blood or cervical secretions intrapartum, or infected breast milk
postpartum [2
]. Second, the mucosa likely participates
in the selection of the genotypic and phenotypic minor variants that
are transmitted in acute infections. Third, the gastrointestinal tract
mucosa is the largest lymphoid organ in the body [3
],
containing the largest number of lymphocytes and macrophages of any
body organ [4
]. Consequently, the enteric mucosa may be
an important reservoir for HIV-1-infected mononuclear cells
[5
]. Moreover, the local abundance of cytokines
[6
] and microbial agents [7
] capable of
up-regulating HIV-1 expression [8
, 9
]
suggests that the mucosa is also a potential site of high-level HIV-1
production. Fourth, the local and systemic immunosuppression induced by
HIV-1 infection predisposes the gastrointestinal tract to a complex
array of opportunistic infections [7
], resulting in
substantial morbidity in the majority of persons who develop AIDS
[10
].
After HIV-1 inoculated onto a mucosal surface crosses the
epithelium, likely by transcytosis [11
], it encounters
lamina propria mononuclear cells. These cells, or possibly epithelial
cells, presumably select from the pool of inoculated variants the
macrophage-tropic species that are transmitted in nearly all mucosally
acquired HIV-1 infections [12
13
14
15
]. This selection is
likely receptor-mediated, but the distribution of CD4 (the primary
receptor for HIV-1), CCR5 [the coreceptor for macrophage-tropic (R5)
viruses] and CXCR4 [the coreceptor for lymphocyte-tropic (X4)
viruses] on intestinal lamina propria cells has not been fully
elucidated. In addition, the biological parameters of HIV-1 replication
in mucosal mononuclear cells have not been fully characterized.
Therefore, to elucidate the role of mucosal mononuclear cells in HIV-1
disease, we have initiated a series of studies that seek to
characterize intestinal (lamina propria) lymphocytes and macrophages
for HIV-1 receptor and coreceptor expression and susceptibility to
infection by R5 and X4 HIV-1.
|
RESIDENT INTESTINAL LYMPHOCYTES AND MACROPHAGES
|
|---|
Current concepts regarding virological events in the mucosa
during HIV-1 disease have been extrapolated largely from studies of the
interaction between blood mononuclear cells and HIV-1. However, lamina
propria lymphocytes and macrophages differ phenotypically and
functionally in many regards from blood lymphocytes and monocytes
[16
, 17
]. Consequently, information
acquired from the study of blood mononuclear cells and HIV-1 does not
accurately reflect mucosal cell-HIV-1 events. Therefore, to study the
interaction between primary mucosal cells and HIV-1, we developed a
technique to isolate and purify lamina propria lymphocytes and
macrophages from normal human small intestinal mucosa. Lamina propria
lymphocytes and macrophages were isolated from jejunal tissue sections
from organ transplantation donors without intestinal or immunological
diseases by tissue digestion using the neutral protease Dispase
[18
]. The lamina propria mononuclear cells were then
separated by counterflow centrifugal elutriation into highly purified
populations of lymphocytes and macrophages [18
,
19
]. The intestinal lymphocytes displayed typical
lymphocyte morphology and phenotype [18
]. Intestinal
macrophages isolated and purified by the same technique displayed the
size distribution, morphological features, ultrastructure, phagocytic
activity, and phenotype of macrophages [18
]. Blood
lymphocytes and monocytes from the same donors were purified by
counterflow centrifugal elutriation [19
] and then
treated with neutral protease according to the tissue digestion
protocol in order for all cell populations to be treated similarly
before study.
Purified intestinal lymphocytes were routinely 
95%
CD3+CD103+ and blood lymphocytes routinely
95% CD3+, and neither population contained detectable
macrophages or monocytes, respectively (Fig. 1
). Approximately 1% of intestinal lymphocytes were B cells, and
about 5% of blood lymphocytes were B cells. Conversely,
HLA-DR+CD13+ intestinal macrophages, which are
CD14- [17
, 18
], and
CD14+HLA-DR+CD13+ blood monocytes
contained no detectable lymphocytes (Fig. 1)
. The intestinal cells did
not express CD83 or display ultrastructural characteristics of
dendritic cells before or after treatment with optimal concentrations
of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor
necrosis factor (TNF-), and interleukin-4 (IL-4).
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Figure 1. Purity of intestinal lymphocytes and macrophages and blood
lymphocytes and monocytes. Cells were isolated from segments of normal
human intestine by enzyme digestion, purified by elutriation, and
analyzed before culture for the indicated surface antigen by flow
cytometry. Results from a representative donor show fluorescence
profiles for purified populations of cells stained with CD-specific
antibodies (solid lines), HLA-DR, or isotype-matched control antibody
(dotted line).
|
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REDUCED PERMISSIVENESS OF INTESTINAL MACROPHAGES TO HIV-1 INFECTION
|
|---|
We recently showed that intestinal macrophages require 1,000-fold
more virus to establish infection in vitro than
monocyte-derived macrophages (Fig. 2
) [20
]. This is consistent with the remarkably low
prevalence (0.06%) of HIV-1 mRNA-expressing macrophages among lamina
propria mononuclear cells in the gastrointestinal tract mucosa of
patients with AIDS [5
]. The marked reduction in the
permissiveness of intestinal macrophages to HIV-1 infection was not
caused by the isolation procedure or reduced CD4 expression. Instead,
intestinal macrophages expressed almost no detectable CCR5 (Fig. 3A
), the principal coreceptor for R5 (macrophage-tropic) viruses,
although both intestinal macrophages and blood monocytes contained
comparable levels of CCR5 mRNA (Fig. 3B)
. Exposure of monocyte-derived
macrophages to HIV-1 or gp120 lead to increased surface expression of
CCR5, but exposure of intestinal macrophages to either HIV-1 or gp120
did not (Fig. 3C)
. These findings suggested that the markedly impaired
permissiveness of intestinal macrophages to HIV-1 was due to the near
absence of macrophage surface CCR5.
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Figure 2. Kinetics and levels of p24 antigen production by HIV-1-inoculated
monocytes (blood-derived macrophages) and intestinal (lamina propria)
macrophages. Cells were cultured for 5 days and then inoculated with
serial dilutions of the indicated HIV-1 R5 (ADA, DJV, or BaL) or X4
(IIIB) isolate and monitored for p24 production. (Reproduced with
permission from ref. 20
).
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Figure 3. CCR5 expression on monocytes (blood-derived macrophages) and intestinal
(lamina propria) macrophages. Cells were analyzed (A) by dual
fluorescence flow cytometry for CCR5/CD13 and CCR5/HLA-DR, (B) by
reverse-transcriptase polymerase chain reaction for CCR5 mRNA, and (C)
by flow cytometry after a 24-h incubation with media alone, LPS (10
µg/mL), HIV-1 (BaL: TCID50 1,000/2.5 x
106 cells/mL), or gp120 (1 µg/mL). Bars represent the
mean ± SD percent of CCR5-positive cells for three
independent experiments. Insets in upper panels of A show the contour
plots for the isotype-matched control antibody. (Reproduced with
permission from ref. 20
.)
|
|
The findings also suggested a paradox in which intestinal
macrophages are down-regulated for permissiveness to HIV-1
[20
], yet acutely transmitted HIV-1 species are nearly
always macrophage-tropic [12
13
14
15
]. Therefore, to confirm
the absence of CCR5 on intestinal macrophages and to elucidate the
potential role of intestinal lymphocytes in early HIV-1 infection, we
characterized purified primary intestinal lymphocytes and macrophages
from the same donors for surface CD4, CCR5, and CXCR4 expression and
then determined the permissiveness of the cells to macrophage-tropic
and lymphocyte-tropic HIV-1.
|
INTESTINAL LYMPHOCYTES, NOT MACROPHAGES, EXPRESS CCR5 AND
CXCR4
|
|---|
Because intestinal macrophages appeared to lack CCR5, we next
investigated primary intestinal lymphocytes for surface CCR5 and CXCR4
expression [21
]. Among fresh intestinal lymphocytes
purified from a representative donor, 10% expressed surface CD4, 92%
CCR5, and 86% CXCR4 (Fig. 4
). Among intestinal macrophages freshly isolated from the same
donor, 9% expressed CD4, but, in sharp contrast to the intestinal
lymphocytes, none expressed detectable CCR5 or CXCR4 (Fig. 4)
. In
addition, incubation of the macrophages with optimal doses of M-CSF,
GM-CSF, IL-6, phorbol myristate acetate (PMA), or lipopolysaccharide
(LPS) for 24 h did not induce expression of either coreceptor.
Blood lymphocytes and monocytes from the same donor expressed CD4 and
both CCR5 and CXCR4 (Fig. 4)
. The presence of CCR5 on blood monocytes
(and on the intestinal and blood lymphocytes) from the same donor
indicated that the absence of surface CCR5 on intestinal macrophages
was not due to expression of the 
32 CCR5 deletion allele. The
frequencies of CD4+, CCR5+, and
CXCR4+ cells in populations of purified intestinal and
unmatched blood mononuclear cells from additional donors (Table 1
) confirmed the presence of CCR5 and CXCR4 on each cell type except
the intestinal macrophages.
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Figure 4. HIV-1 receptor and coreceptor expression on intestinal and blood
mononuclear cells. Intestinal lymphocytes and macrophages and blood
lymphocytes and monocytes from the same donor were purified and stained
for CD4, CCR5, and CXCR4 within 2 h of isolation. The cells were
subsequently analyzed for surface CD4, CCR5, and CXCR4 by flow
cytometry.
|
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|
INTESTINAL LYMPHOCYTES, NOT MACROPHAGES, SUPPORT R5 AND X4
HIV-1 REPLICATION
|
|---|
Having shown that intestinal lymphocytes express CD4, CCR5, and
CXCR4 and that intestinal macrophages express only CD4, we next
investigated the susceptibility of these populations to HIV-1 infection
[21
]. Intestinal lymphocytes (cultured 2 days with
phytohemagglutinin 5 µg/mL and IL-2 24 U/mL) and macrophages
(cultured 5 days in M-CSF 1,000 U/mL) were inoculated in parallel with
R5 (BaL) and X4 (IIIB) isolates of HIV-1 (TCID50 10,000
each). Intestinal lymphocytes supported replication by both BaL and
IIIB (Fig. 5
, left), consistent with their
CCR5+CXCR4+ phenotype. In contrast, intestinal
macrophages, which displayed no detectable CCR5 or CXCR4, were
permissive to neither BaL nor IIIB (Fig. 5
, left). Intestinal
macrophages also did not support replication by additional R5
laboratory isolates (ADA and DJV; TCID50 10,000) and
primary clinical isolates (MDR 24 and JOEL; TCID50 500;
Fig. 6
). Furthermore, culturing the macrophages with GM-CSF, TNF-,
IL-6, PMA, or LPS during or after exposure of the cells to HIV-1 did
not result in detectable p24 production.
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Figure 5. Levels of p24 antigen production in cultures of intestinal and
blood mononuclear cells inoculated with HIV-1. Intestinal lymphocytes
and macrophages (left panel) and blood lymphocytes and monocyte-derived
macrophages (right panel) isolated from the same donor were cultured
for either 2 days (lymphocytes) or 5 days (monocytes/macrophages) and
then inoculated in parallel with an X4 isolate (IIIB) or an R5 isolate
(BaL) of HIV-1 (TCID50 10,000 each) and monitored for p24
production.
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Figure 6. Peak p24 antigen production by intestinal macrophages and
monocyte-derived macrophages inoculated with laboratory and primary
isolates of HIV-1. Intestinal macrophages and blood monocytes isolated
from the same donor were cultured for 5 days, inoculated with
laboratory (ADA and DJV; TCID50 10,000) or primary (JOEL
and MD24; TCID50 500) isolates of HIV-1 and then monitored
for p24 production. Bars correspond to levels of peak p24 antigen
production (day 16).
|
|
We next compared the level of HIV-1 replication in intestinal
mononuclear cells with that of blood lymphocytes and monocyte-derived
macrophages from the same donor. Similar to the intestinal lymphocytes,
blood lymphocytes (cultured in the same conditions as the intestinal
lymphocytes) supported HIV-1 replication by BaL and IIIB (Fig. 5
,
right). Although intestinal lymphocytes were permissive to HIV-1, they
produced less p24 antigen than infected blood lymphocytes. In sharp
contrast, monocyte-derived macrophages inoculated with BaL produced
high levels of p24 (peak 90,000 pg/mL), whereas intestinal macrophages
inoculated with the same doses of HIV-1 produced no detectable p24
(Fig. 5 , right). Neither intestinal macrophages nor monocyte-derived
macrophages supported IIIB replication, consistent with the absence of
CXCR4 on the intestinal macrophages (Fig. 4
; Table 1
) and the lack of
biological function of the CXCR4 receptor on blood monocytes
[22
]. Thus, intestinal lymphocytes, not macrophages,
support HIV-1 replication.
|
SUMMARY
|
|---|
The results summarized above suggest the following sequence of
events in the intestinal mucosa before and during early HIV-1
infection. As circulating CCR5+CXCR4+ blood
lymphocytes and monocytes traffic through the mucosa, they encounter
local chemotactic signals that direct their migration into the lamina
propria. Once in the mucosa, the cells encounter local bacterial
products, such as LPS. The LPS binds to monocyte surface CD14, the
receptor for complexes of LPS and LPS-binding protein, which activates
the cells and causes down-regulation of CCR5 expression
[23
]. Lymphocytes, lacking CD14, would not be
susceptible to the down-modulatory action of LPS. Also, differentiation
of blood monocytes into macrophages may cause down-regulation of
surface CXCR4 [24
], offering a potential explanation, at
least in part, for the impaired expression of CXCR4 on the macrophages.
Whether human small intestinal macrophages differ from colonic
macrophages in the expression of surface CCR5 and CXCR4 is not known.
As the monocytes take up residence in the lamina propria and
differentiate into macrophages, they also lose surface CD14 by
mechanisms that are currently under investigation [17
].
After HIV-1 inoculated onto a mucosal surface crosses the epithelium,
it encounters CD4+ mononuclear cells in the underlying
lamina propria. Whereas intestinal macrophages were presumed to be the
initial target cell for R5 HIV-1 entry, the findings presented above
indicate that the only resident mononuclear cells capable of supporting
R5 viral replication in the mucosa are lamina propria lymphocytes, not
macrophages. Although dendritic cells play an important role in the
pathogenesis of early HIV-1 infection in extraintestinal lymphoid
tissue [25
, 26
], their role in intestinal
HIV-1 infection is less likely since, as shown here, they appear not to
be present in intestinal lamina propria. Dendritic cells are present in
organized lymphoid structures (i.e., Peyer’s patches) of the mouse
small intestine [27
], but such structures are uncommon
in the proximal small intestine of humans. Thus, the presence of CCR5
on intestinal lymphocytes and their susceptibility to R5 virus
infection suggest that after initial selection, possibly by intestinal
epithelial cells, the R5 species that enters the lamina propria first
infects lymphocytes.
That intestinal lymphocytes, not macrophages, are permissive to HIV-1
infection is consistent with in vivo observations in both
humans and macaques. As we have shown in humans with AIDS, mucosal
macrophages productively infected with HIV-1 are rare, with a
prevalence of 0.06% among lamina propria mononuclear cells
[5
]. In addition, the majority of cells containing HIV-1
mRNA in nongastrointestinal lymphoid tissue (e.g., tonsils) are not
macrophages but other lymphoid mononuclear cells [28
].
In macaques, simian immunodeficiency virus (SIV) inoculated
intravenously [29
], intravaginally [30
],
and orally [31
] first infects mucosal lymphocytes and
the subsequent local replication occurs predominantly in lymphocytes;
infected intestinal macrophages are rare during early infection
[29
30
31
]. Also, CCR5+ macrophages constitute
<1% of rectal lamina propria macrophages in macaques
[32
].
Thus, taken together, these findings indicate that resident macrophages
play a less important role in the pathogenesis of early mucosal HIV-1
infection than previously suspected. Instead, intestinal lymphocytes
appear to be the initial target cell for mucosally acquired R5 HIV-1
and the predominant source of HIV-1 production among resident
mononuclear cells in the gastrointestinal tract mucosa.
|
ACKNOWLEDGEMENTS
|
|---|
This study was supported by National Institutes of Health grants
DK-47322, AI-41530, DE-72621, and by the Research Service of the
Department of Veterans Affairs.
|
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L. J. Montaner, C.-F. Perno, and S. Crowe
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TOP
ABSTRACT
INTRODUCTION
