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Journal of Virology, August 2000, p. 6720-6724, Vol. 74, No. 15
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
CD4-Independent, CCR5-Dependent Simian
Immunodeficiency Virus Infection and Chemotaxis of Human
Cells
Sujatha
Iyengar,1
David H.
Schwartz,1,*
Janice
E.
Clements,2 and
James
E. K.
Hildreth3
Department of Molecular Microbiology and
Immunology, School of Public Health,1 and
Departments of Pharmacology3 and
Comparative Medicine,2 School of
Medicine, Johns Hopkins University, Baltimore, Maryland 21205
Received 26 July 1999/Accepted 21 April 2000
 |
ABSTRACT |
Most simian immunodeficiency virus (SIV), human immunodeficiency
virus type 2 (HIV-2), and HIV-1 infection of host peripheral blood
mononuclear cells (PBMCs) is CD4 dependent. In some cases, X4 HIV-1
chemotaxis is CD4 independent, and cross-species transmission might be
facilitated by CD4-independent entry, which has been demonstrated for
some SIV strains in CD4
non-T cells. As expected for
CCR5-dependent virus, SIV required CD4 on rhesus and pigtail macaque
PBMCs for infection and chemotaxis. However, SIV induced the chemotaxis
of human PBMCs in a CD4-independent manner. Furthermore, in contrast to
the results of studies using transfected human cell lines, SIV did not
require CD4 binding to productively infect primary human PBMCs.
CD4-independent lymphocyte and macrophage infection may facilitate
cross-species transmission, while reacquisition of CD4 dependence may
confer a selective advantage for the virus within new host species.
| |
INTRODUCTION |
Recent evidence suggests that human
immunodeficiency virus type 1 (HIV-1) arose from simian
immunodeficiency virus strain cpz (SIV cpz) by transmission from
chimpanzees to humans after prior cross-species transmission from
monkeys to chimpanzees (9, 11). In contrast, all available
evidence indicates that HIV-2 made the transition from monkeys to
humans directly, without a chimpanzee intermediary (1, 2, 8,
10). These cross-species jumps raise questions about ongoing
transmissions and the adaptations required of the virus during
transition from one host species to another.
Our previous studies have shown that HIV-1 infection and
envelope-induced chemotaxis can be dissociated with respect to CD4 dependence. Specifically, we (12) and others (16)
have found that CXCR4 binding (X4) gp120 can induce chemotaxis without
binding to CD4 or even requiring the presence of CD4 on the cell
surface whereas infection by X4 HIV requires cell surface CD4. In
contrast, both chemotaxis and infection by CCR5 binding (R5) HIV-1
envelope and virus, respectively, are CD4 dependent (12,
18). Regardless of the cell type infected, SIV preferentially
exploits CCR5 rather than CXCR4 as a CD4-dependent coreceptor (3,
13-15), and many strains of SIV can utilize CCR5 on non-T cells
in a CD4-independent manner (4, 5).
Given these diverse results and the role of coreceptor usage in
restricting cross-species host range tropism, we set out to systematically compare SIV coreceptor requirements for viral infection and virus-induced chemotaxis in monkey and human cells. We chose two
strains of SIV known to use CCR5 for entry into macaque cells: SIVmac239 is considered a prototypic virus infecting T-cell lines (such
as CEMx174, in which we passage the virus), while SIV 17E-Fr is a
chimeric recombinant of SIVmac239 containing the envelope of
neurotropic SIV-17E (capable of infecting astrocytes, glial cells, and
brain endothelial cells [6]). SIV 17E-Fr is dually tropic, and when passaged in CEMx174 cells it maintains its tropism for
primary macaque macrophages (6). Despite envelope
differences and distinct patterns of tropism in purified cell
types, both SIVmac239 and SIV 17E-Fr infect monkey peripheral
blood mononuclear cells (PBMCs) in vitro with high efficiency. In the
present study, infection and chemotaxis were assessed in macaque and
human cells.
| |
MATERIALS AND METHODS |
Cells and reagents.
Human and macaque (rhesus and pigtail)
PBMCs were obtained by Ficoll-Hypaque centrifugation or by Percoll
gradient centrifugation (Sigma Chemical Co., St. Louis, Mo.). The PBMCs
were stimulated for 3 days with 5 µg of phytohemagglutinin (PHA),
(GIBCO BRL, Gaithersburg, Md.) per ml in RPMI 1640 supplemented with
10% fetal calf serum (FCS) and 2 U of interleukin-2 (IL-2) (Boehringer
Mannheim, Indianapolis, Ind.) per ml. CD4+ or
CD8+ cells were enriched by negative depletion using,
respectively, anti-CD8 or anti-CD4 magnetic beads (Dynal, Lake Success,
N.Y.) at saturating concentrations. The purity of T-cell subsets was determined for each subset by flow cytometric analysis of cells immunostained with 20 µg of anti-CD4 and anti-CD8 monoclonal
antibodies (MAbs) (Coulter Immunology, Hialeah, Fla.) per ml detected
with fluorescein isothiocyanate-conjugated goat anti-mouse
immunoglobulin G (IgG) (Jackson Immunoresearch Laboratories, Bar
Harbor, Maine). Anti-CXCR4 (12G5), anti-CCR5 (2D7), and HIV-blocking
(Leu3a, SIM4) and HIV-nonblocking (SIM7) anti-CD4 MAbs were obtained
from the National Institutes of Health AIDS Reagent Program. All were
used at 10 µg/ml. Beta chemokines (RANTES, MIP1-
, and MIP-1
)
and alpha chemokines (SDF1- and SDF1-) were from R&D Systems,
Minneapolis, Minn., and were used at 200 ng/ml. Soluble CD4-Ig
(Genentech Inc., South San Francisco, Calif.) was used at 10 µg/ml.
Virus infection.
SIV17E-Fr and SIVmac239 were passaged in
CEMx174 cells and purified from cell culture supernatants by sucrose
density gradient centrifugation. PBMCs were stimulated with 5 µg of
PHA per ml, aliquoted into tubes at 107 cells/ml of RPMI
1640-10% FCS-IL-2, and pretreated with antibodies to CD4, CXCR4, or
CCR5 or with alpha or beta chemokines for 30 min on ice. The cells were
then infected with 103 50% tissue culture infective doses
of SIV 17E-Fr or SIVmac239 for 2 h with shaking at 37°C. In one
group, the virus was pretreated with soluble CD4-Ig for 30 min on ice
before being used to infect cells. After infection, the cells were
washed free of virus and plated at 2 × 106 per well
in triplicate wells of a 24-well culture plate.
A 1-ml volume of supernatant was collected from a total volume of 2 ml
and replenished with an equal volume of fresh medium on days 0, 3, and
7 postinfection, and 200 µl of that 1-ml volume was used for the p27
assay. The remaining supernatant was frozen at 
80°C freezer. The
cell cultures were replenished with 1 ml of fresh medium on day 7 and
again harvested on days 10 and 14. Supernatants collected on days 0, 3, and 7 were assayed for p27 by enzyme immunoassay (EIA) (Coulter
Immunology). In all wells, day 0 (2 h after the final wash) and day 3 supernatant samples assayed in parallel with day 7 samples contained
p27 levels below the positive cutoff. Day 0 concentrations were
invariably <5 pg/ml (the limit of assay detection), while day 3 samples were generally higher but always <20 pg/ml, the calculated
cutoff value for reliable positivity using the manufacturer's
guidelines. Day 10 and 14 values appeared to follow the same trends
among groups as day 7 values, but the absolute values were higher and
frequently off-scale for linear quantitation without further dilution.
Chemotaxis assay.
CD4+ and CD8+
PBMCs obtained after PHA-IL-2 activation were stained with MAbs to
CD4, CD8, CXCR4, and CCR5, and their expression levels were determined
by fluorescence-activated cell sorter analysis. Cells (20,000/well)
were labeled with 5 µM calcein (Molecular Probes) and placed above 5 µm-pore-size filters overlying medium alone, chemokines, or virus in
serial dilutions (0.1 to 100 ng/ml) in 96-well microchemotaxis chambers
(Neuroprobe, Gaithesburg, Md.). After a 2-h incubation at 37°C,
labeled cells in the lower chamber were read in fluorimeter at
excitation and emission wavelengths of 480 and 530 nm, respectively.
Migration index (MI) is expressed as (experimental medium cell
fluorescence/medium cell fluorescence). The results are expressed as
mean ± standard deviation for triplicate experiments. Because
absolute numbers of migrating cells can vary substantially by donor and
between experimental runs, results are normalized against migrating
cells in control medium (RPMI 1640 plus 0.5% FCS) and expressed as the
ratio of absolute numbers of cells, or MI.
| |
RESULTS AND DISCUSSION |
CD4-dependent infection and chemotaxis of macaque PBMCs by
SIV.
Macrophage-tropic SIV 17E-Fr, T-cell-tropic SIVmac239, and
recombinant SIVmac239 envelope were analyzed for their ability to
induce chemotaxis of PHA-IL-2-activated PBMCs from pigtail macaques in
a 96-well microchemotaxis chamber assay. Purified recombinant MIP1-
was used at 10 ng/ml as a positive control. Both strains of virus and
the recombinant envelope protein induced dose-dependent chemotactic
activity (data not shown) with maximal chemotaxis at 10 ng of p27/ml
(Fig. 1A).
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FIG. 1.
Exposure of PHA-IL-2-activated pigtail macaque PBMCs to
SIVmac239 or SIV 17E-Fr causes chemotaxis (A) and infection (B).
Chemotaxis to SIV or MIP1- was inhibited by pretreatment of cells
with 10 µg of anti-CD4 MAb (Leu3A) or anti-CCR5 MAb (2D7) per ml for
30 min on ice. Alternatively, purified virus was pretreated with
sCD4-Ig (10 µg/ml) for 30 min on ice before use in the chemotaxis
assay, as described in Materials and Methods. Macaque CD8+
cells isolated by negative depletion with anti-CD4 magnetic beads
(>85% CD8+, <2% CD4+ cells) did not migrate
in response to SIVmac239 or SIV 17E-Fr. CD4+ and
CD8+ lymphocytes expressed comparable levels of CXCR4 and
CCR5 and had similar migratory dose-response curves to SDF1- and
MIP1-. Infection with 103 50% tissue culture infective
doses of SIVmac239 or SIV 17E-Fr was inhibited by pretreatment of cells
with 10 µg of MAbs to CD4 or CCR5 per ml or 200 ng of the beta
chemokines (RANTES, MIP1- and MIP1-) per ml for 30 min on ice but
not with anti-CXCR4 MAb (12G5) or 200 ng of the alpha chemokines
(SDF1- and SDF1-) per ml. Treatment of purified virus with
sCD4-Ig for 30 min on ice prior to infection of cells was also
inhibitory. Supernatants were assayed for p27 on day 7. Results
represent the mean ± standard error of the mean of three
experiments. Similar trends were observed on days 10 and 14, although
absolute values of p27 were higher.
|
|
Two approaches were used to determine the requirement for CD4 and CCR5
in this signaling process. In the first approach, various
soluble
reagents were added to cells and/or virus inocula at high
concentrations to competitively inhibit envelope-receptor interactions.
Chemotaxis assays were performed with activated PBMCs that were
untreated (positive control), pretreated with anti-CD4, or pretreated
with anti-CCR5 antibodies. CD4-specific (SIM4 or Leu3a) and
CCR5-specific
(2D7) antibodies that block virus binding and infection
(blocking
MAbs) had an inhibitory effect on the chemotactic property of
SIV (Fig.
1A). In contrast, anti-CD4 (SIM7) and anti-CXCR4 (12G5)
MAbs
that do not interfere with virus binding or infection (nonblocking
MAbs) did not inhibit the chemotactic response of PBMCs to SIV
(data
not shown). Consistent with an essential role for CD4 in
SIV
envelope-mediated signaling through CCR5 on pigtail macaque
PBMCs,
pretreatment of virus with 10 µg of soluble CD4-IgG fusion
protein
per ml was shown to have an inhibitory effect on SIV-induced
chemotaxis
(Fig.
1A).
The second approach to defining the role of CD4 in this combination of
virus and macaque cells involved the removal of CD4
+ cells
from the PBMC and assessment of chemotaxis in the residual
nonadherent
population (85% CD8
+, <2% CD4
+). As seen
from Fig.
1A, PBMCs depleted of CD4
+ cells were
unresponsive to both strains of SIV but migrated normally
in response
to MIP1-
. Recombinant SIVmac239 envelope paralleled
SIV virions in
inducing chemotaxis of pigtail macaque PBMCs in
a CD4- and
CCR5-dependent manner (data not
shown).
Similar requirements for CD4 and CCR5 were observed with experiments
analyzing SIV infection of pigtail macaque PBMCs (Fig.
1B). In
infection experiments, additional groups (cells pretreated
with alpha
and beta chemokines or CXCR4-specific MAb 12G5) were
included to
confirm expected coreceptor usage. Similar results
were obtained when
rhesus rather than pigtail macaque cells were
used in the above
chemotaxis and infection experiments (Fig.
2).
Again, CD4-depleted rhesus macaque
cells did not migrate in response
to SIV virions (Fig.
2A) or envelope
exposure (data not shown).
Therefore, we found that SIVmac239 and SIV
17E-Fr attract and
productively infect macaque PBMCs in a
CD4-dependent, CCR5-dependent
manner.
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|
FIG. 2.
Exposure of PHA-IL-2-activated rhesus macaque PBMCs to
SIVmac239 or SIV 17E-Fr causes chemotaxis (A) and infection (B).
Reagents and assays of chemotaxis and infection were as described for
Fig. 1.
|
|
CD4-independent infection and chemotaxis of human PBMCs by
SIV.
To determine if similar receptor requirements are retained by
SIV in human cells, the chemotaxis and infection experiments described
above were performed using PHA-IL-2-activated human PBMCs. Both
SIVmac239 and SIV 17E-Fr induced dose-dependent chemotactic activity,
illustrated at maximal chemotaxis with 10 ng of p27/ml in Fig.
3A. Neither SIV-induced chemotaxis (Fig.
3A) nor infection (Fig. 3B) of human PBMCs was inhibited by
pretreatment of cells with any of the blocking or nonblocking anti-CD4
MAbs described above. However, the anti-CCR5 MAb was inhibitory for
SIV-induced chemotaxis (Fig. 3A) and infection of human PBMCs (Fig.
3B). Additional groups that included cells pretreated with alpha or
beta chemokines confirmed the requirement for CCR5 during SIV infection
of human PBMCs (Fig. 3B).
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|
FIG. 3.
Anti-CD4 MAb and sCD4-Ig do not inhibit chemotaxis (A)
or infection (B) of activated human CD4+ PBMCs with
SIVmac239 or SIV 17E-Fr, whereas anti-CCR5 MAb inhibits chemotaxis (A)
and infection (B). Infection with both viruses was also inhibited by
beta chemokines, but not by SDF1-, SDF1-, or anti-CXCR4 MAb.
Reagents and assays were as described for Fig. 1. Human
CD8+ cells isolated by negative depletion with anti-CD4
magnetic beads (>85% CD8+, <2% CD4+ cells)
migrated in response to SIVmac239 or SIV 17E-Fr as well as to
MIP1-.
|
|
To further establish surface CD4 as nonessential on human cells for SIV
envelope-mediated signaling through CCR5, human PBMCs
were
immunomagnetically depleted of CD4
+ cells and the remaining
cells (<2% CD4
+, 85% CD8
+) were used in
chemotaxis assays with recombinant envelopes and
purified virions. Flow
cytometry revealed comparable expression
by activated CD4
+
and CD8
+ cells of CXCR4 or CCR5 and similar dose-response
curves of CD4
+ and CD8
+ cells migrating toward
SDF1-
or MIP1-
(data not shown). The
<2% CD4
+ cells
remaining in the CD4-depleted population cannot account
for the
observed high migration indices, since MIs of >6 represent
migration
of more than half the input cells (Fig.
3A). For both
strains of
SIV and recombinant SIVmac239 envelope, chemotaxis
of
CD8
+ cells was comparable to that of whole PBMCs. Thus, CD4
was not
necessary for the SIV strains to induce chemotaxis or
productively
infect human PBMCs (Fig.
3). This contrasts with the CD4
requirement
for CCR5-mediated infection or chemotaxis of pigtail and
rhesus
macaque PBMCs (Fig.
1 and
2).
Our results have implications with respect to the evolution of HIV-2
and HIV-1 from SIV and SIVcpz, respectively. Specifically,
CD4-independent infection of PBMCs might have facilitated initial
cross-species transmission, while subsequent reacquisition of
CD4
dependence for infection of lymphocytes may have ultimately
conferred a
selective entry or growth advantage. This would account
for the
observed CD4 dependence of SIV in macaque PBMCs and of
HIV-2 in human
PBMCs. Facilitation of cross-species transmission
by CD4 independence
could occur at two levels. First, it would
obviate the need for virus
to bind equally well to the new CD4
molecule of the new host, which
might have important differences
at the binding site. This would permit
virus to enter CD4-positive
cells without necessarily binding well to
their surface CD4. Second,
it raises the possibility of entry into
CD4-negative cells as
initial or temporary hosts for early
replication.
Evidence to date from other laboratories indicates that, at a molecular
level, SIV envelope binding to human CD4 domains occurs
with good
affinity (
7,
17). Therefore, CD4 independence presumably
would not be required for nonhuman-primate-to-human transmission
of the
SIV strains studied here. However, we do not know the binding
capacity
of the originally transmitted ancestral SIV for the originally
infected
human host CD4. If the affinity was low, CD4 independence
may have been
important. Alternatively, CD4-independent infection
of CD4
+
human PBMCs may simply be an epiphenomenon related to the ability
of
transmitted SIV to infect CD4
cells. This latter aspect
may have been even more important in
facilitating interspecies jumps
and may be reflected in the relative
ease with which many strains of
SIV and HIV-2 can infect brain
capillary endothelial cells and other
CD4
cells (
4).
At first blush, our results are not concordant with those of Edinger et
al. (
5), who found that rhesus macaque CCR5 was
generally
more supportive than human CCR5 of CD4-independent infection
with
various SIV strains, due to a single amino acid difference
in the N
terminus. In particular, these authors found that SIVmac239
envelope-bearing virus was highly dependent on the presence of
CD4,
irrespective of whether human or rhesus macaque CCR5 was
coexpressed,
while SIV 17E-Fr entered at a moderately reduced
level in the absence
of surface CD4, using rhesus CCR5 more effectively
than it used human
CCR5.
The explanation for these different results probably lies in the choice
of target cells. We used primary, untransformed PBMCs
from humans and
macaques throughout, while Edinger et al. (
5)
used 293T cell
lines transiently transfected with various highly
expressing chemokine
receptor plasmids. The entry requirements
for tumor cell lines
overexpressing transfected receptors may
differ from those for viral
entry into primary activated lymphocytes.
In addition, the previous
viral challenge used envelope chimeras
from various SIV strains on a
luciferase-expressing NL-LucR-E-backbone
whereas ours used cultured
infectious virions with p27 production
as the infection
readout.
Fomsgaard et al. (
7) reported that several strains of SIV
used CD4 binding regions from African green monkeys, pigtail
macaques,
or humans indiscriminately when transfected into macaque-derived
transformed CMMT cells, in spite of predicted structural differences.
Nevertheless, when untransformed PBMCs are used, interspecies
differences in CD4 and CCR5 may be sufficient to account for our
results. In addition to initial binding constraints, CCR5- and/or
CD4-mediated signal transduction may play important roles in viral
entry into primary (as opposed to immortalized) cells, in which
case
small interspecies differences in coreceptor sequences or
downstream
transduction proteins could also contribute to restricted
tropism.
In any case, preliminary unpublished data suggest that CD4 independence
is a transient phenomenon during long-term in vitro
passage, suggesting
a major selective advantage for targeting
of CD4
+ host
cells, even in the absence of an immune response. We are
currently
examining the relative rates of infection in CD4
+ and
CD4
PBMCs during the earliest rounds in vitro infection
to determine
the degree of replicative advantage conferred upon SIV by
integration
into CD4
+ lymphocytes and
macrophages.
| |
ACKNOWLEDGMENTS |
This work was supported by Public Health Service grants
R21-A144725 and RO1-AI31806 from the National Institute of Allergy and
Infectious Diseases.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Molecular Microbiology and Immunology, 615 N. Wolfe Street, Johns
Hopkins School of Public Health, Baltimore, MD 21205-2179. Phone: (410) 955-3175. Fax: (410) 955-0105. E-mail: dschwart{at}jhsph.edu.
| |
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Journal of Virology, August 2000, p. 6720-6724, Vol. 74, No. 15
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
