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Journal of Virology, July 2000, p. 6689-6694, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
CD4-Independent Infection of Two
CD4
/CCR5/CXCR4+ Pre-T-Cell
Lines by Human and Simian Immunodeficiency Viruses
Alessandra
Borsetti,1,*
Cristina
Parolin,2
Barbara
Ridolfi,1
Leonardo
Sernicola,1
Andrea
Geraci,1
Barbara
Ensoli,1 and
Fausto
Titti1
Laboratory of Virology, Istituto Superiore di
Sanità, Rome,1 and Department of
Histology, Microbiology and Medical Biotechnologies, University of
Padua, Padua,2 Italy
Received 30 December 1999/Accepted 24 April 2000
 |
ABSTRACT |
The infection of CD4-negative cells by variants of tissue
culture-adapted human immunodeficiency virus type 1 (HIV-1) or HIV-2 strains has been shown to be mediated by the CXCR4 coreceptor. Here we
show that two in vitro-established
CD4
/CCR5/CXCR4+ human
pre-T-cell lines (A3 and A5) can be productively infected by wild-type
laboratory-adapted T-cell-tropic HIV-1 and HIV-2 strains in a
CD4-independent, CXCR4-dependent fashion. Despite the absence of CCR5
expression, A3 and A5 cells were susceptible to infection by the simian
immunodeficiency viruses SIVmac239 and SIVmac316. Thus, at least in A3
and A5 cells, one or more of the chemokine receptors can efficiently
support the entry of HIV and SIV isolates in the absence of CD4. These
findings suggest that to infect cells of different compartments, HIV
and SIV could have evolved in vivo to bypass CD4 and to interact
directly with an alternative receptor.
| |
TEXT |
The entry of human immunodeficiency
virus type 1 (HIV-1) into target cells is initiated by the binding of
the viral envelope (Env) protein gp120 to the CD4 receptor present on
the cell surface and, subsequently, to a coreceptor belonging to the
chemokine receptor family (1, 4, 7, 10, 37). HIV tropism, in fact, is strongly related to coreceptor usage. Studies with recombinant HIV-1 Env have indicated that differences in the sequence of the V3
loop of gp120 are sufficient to determine whether Env binds to CCR5 or
CXCR4 (4, 7).
To enter target cells, simian immunodeficiency virus (SIV) isolates can
use CCR5 but not CXCR4, CCR2b, CCR3, CCR1, or CCR4. Several orphan
receptors, including gpr1, gpr15, and strl33, can also be exploited as
entry cofactors by SIV, and specific changes in the V3 loop can
influence the specific chemokine receptor used by different SIV
variants (6, 10, 11, 14, 28, 29).
It is well established that CD4 is the main receptor for both HIV and
SIV, and it has been proposed that a CD4-induced change in gp120
conformation is necessary for correct binding to the chemokine
receptors. In fact, in the absence of CD4, the V3 loop is not correctly
exposed to allow the direct binding of gp120 to chemokine receptors
(2, 34, 37).
Recent studies have shown that some variants of HIV-1 and HIV-2
cultured in the laboratory can infect both lymphoid and nonlymphoid cells in the absence of CD4, indicating that these viruses can utilize
coreceptors without a prior CD4 interaction (2, 9, 15, 20).
In particular, HIV-1 and HIV-2 are able to infect CD4-negative cells,
utilizing CXCR4 as a primary receptor (9, 12, 24, 26).
Moreover, it has been demonstrated that while different SIV strains can
infect CD4-negative cells by using CCR5, gpr15 supports the
CD4-independent infection by viruses with SIVmac316 and SIVmac316BSS
envelope glycoproteins but does not support a CD4-independent infection
by viruses with the SIVmac239 envelope glycoprotein (28). By
contrast, the utilization of gpr1, strl33, and CCR8 is strictly CD4
dependent (10, 18, 29).
In this study we examined the ability of two highly undifferentiated,
in vitro-established
CD4/CCR5/CXCR4+ human T-cell
lines (A3 and A5) to support infection by wild-type laboratory-adapted
T-cell-tropic HIV-1, HIV-2/ROD10, and SIV.
The A3 and A5 cell lines can be infected by HIV-1, HIV-2, or SIV in
the absence of CD4.
A3 and A5 are highly undifferentiated T-cell
lines derived from in vitro cloning of peripheral blood mononuclear
cells of an asymptomatic HIV-1-seropositive subject (32). No
HIV-1 sequence was ever detected in A3 and A5 cells by nested PCR of
cell lysates using specific primers for the gag,
pol, env, vpu, and nef
regions (5, 32), by coculture with susceptible cells, or by
determination of p24 production (data not shown). PCR analysis showed
the absence of coinfecting viruses that could have been present in the
HIV-1-infected patient, including human T-cell lymphotropic virus type
1 (HTLV-1) (36); cytomegalovirus; adenovirus; Epstein-Barr;
herpesvirus types 1, 2, 7, 8, and 9 (25); JC virus; and BK
virus (22) (data not shown).
Fluorescence-activated cell sorter analysis of A3 and A5 cells using a
CD4 panel of monoclonal antibodies that recognize different epitopes of
the CD4 molecule (Q4120, D4056, L120, Q4116, RFT4, SK3, MT310, RPAT4,
and OKT4a) showed no CD4 cell surface expression. Furthermore,
intracellular staining with different CD4 monoclonal antibodies on
permeabilized cells and radioimmunoprecipitation assays failed to show
the presence of intracellular CD4 protein, despite the detection of CD4
mRNA by reverse transcriptase (RT) PCR in both the A3 and A5 cell lines
(data not shown).
To assess whether these CD4
T-cell lines were susceptible
to HIV-1 or SIV infection, A3 and A5 cells were infected with
HIV-1/HXBc2,
HIV-2/ROD10, SIVmac239, or SIVmac316 at a multiplicity of
infection
of 0.01 50% tissue culture infective dose/cell for 2 h
at 37°C.
Cells were then washed and cultured for an additional 2 weeks.
Infection was detected by measuring the levels of viral p24 in
the culture supernatants at different time points postinfection
(p.i.).
As shown in Fig.
1A, a
productive replication of HIV-1,
HIV-2, and SIV strains occurred
rapidly and in the absence of
syncytium formation. In addition,
cell-free supernatants from
these cultures infected Jurkat, C8166,
SupT1, and CEMx174 cells,
as shown by p24 detection in the cell
supernatants and syncytium
formation 24 h p.i. (data not shown).
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FIG. 1.
Infection of the CD4-negative A3 and A5 cell lines by
HIV-1, HIV-2, and SIVmac239. (A) Replication kinetics of HIV-1, HIV-2,
and SIVmac239. (B) A3, A5, SupT1, and HSB-2 cells were preincubated in
culture medium with 50 µg of either the anti-human CD4 monoclonal
antibody Q4120 or the isotype control per ml at the indicated
concentrations prior to the addition of cell-free HIV-1/HXBc2,
HIV-2/ROD10, or SIVmac239 (multiplicity of infection of 0.01 50%
tissue culture infective dose/cell) and maintained in culture with the
monoclonal antibody for 4 days. On day 4, p24 core protein levels in
the culture supernatants were determined. CD4-positive SupT1 and
CD4-negative HSB-2 cells were included as controls. The experiment
shown is representative of three independent experiments. (C) Infection
of A3 and A5 cells by HIV-1 is independent of the CD4 molecule, as
shown by the entry of wild-type and 368D/R gp120 mutant HXBc2 virus in
both cell lines. Comparable amounts of cell lysates, after normalization to
total protein content with the Micro BCA protein assay (Pierce), were
used for the assays. CAT activity was calculated as the ratio of the
amount of acetylated forms of chloramphenicol (upper spots) to that of
the unacetylated form (bottom spots). SupT1 and HSB-2 cells were
included as controls. The experiment shown is representative of three
independent experiments.
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Previous evidence suggested that laboratory-adapted T-cell-tropic
viruses interact with the cell surface CD4 or soluble CD4,
resulting in
the enhanced infectivity of cultured cells even in
the presence of a
small amount of this receptor (
16). To exclude
the
possibility of viral entry by the CD4 molecule, A3, A5, and
SupT1 cells
were incubated with 50 µg of an anti-human CD4 monoclonal
antibody
(Q4120) per ml or the same concentration of an isotype-matched
control
antibody prior to the addition of the virus to the cells.
After 12 h, cells were washed and cultured in the presence of
the antibodies. On
day 4 p.i. the concentration of p24 in the
culture supernatants
was determined. As expected, the addition
of a saturating concentration
of anti-CD4 antibody inhibited the
infection of SupT1 cells as measured
by the release of p24, whereas
it did not affect HIV-1, HIV-2, or SIV
infection of A3 and A5
cells. No p24 was detected when HSB-2 cells were
infected with
different viruses (Fig.
1B). Similar results were
obtained when
cells were incubated with 100 µg of the anti-CD4
monoclonal antibody
per
ml.
Entry of HIV-1 into A3 and A5 cells is not affected by changes in
the CD4-binding domain of gp120.
It has been previously shown that
the mutation at residue 368 in the gp120 glycoprotein dramatically
reduces the ability of this protein to form syncytia with target cells
or to complement replication of an env-defective virus.
To confirm that the infection of A3 and A5 cells by laboratory-adapted
HIV isolates was independent from the CD4 molecule,
we used a defective
HIV-1 genome whose ability to infect is dependent
on the ability of
envelope glycoproteins to support in
trans virus
transmission either in a cell-free fashion or in a combined cell-free
and cell-to-cell manner. Since the defective HIV is capable of
only one
cycle of replication, the
env complementation assay allowed
us to quantitatively measure the efficiency at which different
envelope
glycoproteins can mediate early phases of virus infection
(
4). To produce recombinant HIV-1 virions, 293 cells were
cotransfected
with the pHXBH10
envCAT plasmid, containing an HIV-1
provirus
with a deletion in the
env gene and the
chloramphenicol acetyltransferase
(CAT) gene replacing the
nef gene, and the pSVIII plasmid, encoding
wild-type or
mutant envelope glycoproteins. To assess whether
infection of A3 and A5
cells was independent of the CD4 molecule,
a mutant with a change at
residue 368 of the prototypical HXBc2
gp120 glycoprotein was also
used.
It has been shown previously that mutation of D to R at position 368 (368D/R mutation) reduces the CD4-binding ability of
HIV-1
glycoproteins as well their ability to complement virus
entry
(
31). Recombinant viruses were harvested 72 h after
transfection
of 293 cells, normalized to 25,000 cpm of RT activity, and
incubated
with A3, A5, SupT1, or HSB-2 cells. CAT activity was then
measured
in the target cells 60 h after infection, providing an
assessment
of the abilities of the cells to support the entry of HIV-1
variants
containing different envelope glycoproteins. Comparable
amounts
of cell lysates, after normalization to total protein content
with the Micro BCA protein assay (Pierce), were used for CAT assays.
CAT activity was calculated as the ratio of the amount of acetylated
forms of chloramphenicol to that of the unacetylated form. Figure
1C
shows that the entry of 368D/R mutant virus into A3 and A5
cells was as
efficient as that of the wild-type virus. By contrast,
the entry of
368D/R mutant virus into SupT1 cells was less successful
than that of
the wild-type virus. No entry of wild-type or mutant
virus was detected
in HSB-2 cells. These results indicated that
the efficiency of
infection of A3 and A5 cells by HIV-1 is not
affected by the absence of
the CD4 molecule on the cell
membrane.
Coreceptor use by HIV and SIV strains for entry into A3 and A5
cells.
HIV entry is dependent not only on the surface expression
of the CD4 molecule but also on the expression of chemokine
coreceptors, such as CXCR4 and CCR5. To determine the surface
expression levels of these chemokine receptors, the A3 and A5 cell
lines were analyzed by flow cytometry using monoclonal antibodies
specific for human CXCR4 (12G5), CCR5 (2D7), CXCR1 (5A12), and CXCR2
(6C6). CXCR4 was expressed at high levels in both clones, whereas no
expression of CCR5, CXCR1, or CXCR2 was detected (data not shown). In
agreement with these results, RT-PCR analysis revealed that A3 and A5
cells expressed high levels of CXCR4 but did not express CCR5. In
addition, both cell lines expressed detectable levels of CCR8, gpr1,
strl33, gpr15, ebi1, and ebi2 mRNA compared with controls. mRNAs coding for CCR2b, CCR3, apj, rdc, dez, and gpr4 were not expressed (data not shown).
Expression of chemokine receptor mRNAs does not necessarily establish
the expression of the proteins on the cell surface,
which is essential
for viral entry. Therefore, we evaluated the
possibility that the
previously tested chemokine receptors could
still support the entry of
HIV-1 and SIV into A3 and A5 cells.
As mentioned above, pseudotyped
CAT-expressing recombinant HIV-1
allows the quantitation of the
efficiency of viral entry into
susceptible cells. CAT-expressing
recombinant HIV-1 bearing the
envelope glycoproteins derived from
laboratory-adapted T-cell-tropic
(HXBc2 and MN), macrophage-adapted
(ADA), T-cell-tropic primary
(ELI), or dualtropic (89.6) HIV-1 isolates
or from SIVmac239 or
SIVmac316 were therefore used to infect A3 and A5
cells. Figure
2A shows that the
recombinant viruses containing the HXBc2 and
MN glycoproteins were able
to infect A3 and A5 cells with comparable
efficiencies. In contrast,
viruses containing ADA, ELI, and 89.6
envelope glycoproteins were
unable to infect A3 and A5 cells.
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FIG. 2.
CAT activity in the A3 and A5 cell lines after
incubation with recombinant viruses containing the HXBc2, MN, 89.6, ELI, or ADA envelope glycoprotein or with SIVmac239 or SIVmac316
envelope glycoprotein. CEMx174 and SupT1 cells were used as controls.
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These results might reflect the chemokine receptor expression pattern
observed in A3 and A5 cells. Thus, a CD4-independent
infection of A3
and A5 cells by the T-cell-line-adapted virus
could occur mainly via
CXCR4, whereas it is possible that primary
strains need a prior
interaction with a specific coreceptor in
order to infect target
cells.
An efficient infection of these cells by recombinant viruses containing
SIVmac239 and SIVmac316 envelope glycoproteins was
also observed (Fig.
2B). Since A3 and A5 cells do not express
CCR5 intracellularly or at
the cell surface level, other coreceptors,
including strl33, gpr1,
gpr15, and CCR8, could be involved in
the CD4-independent entry of SIV
into these cells. These results
indicated that laboratory-adapted
T-cell-tropic viruses (HXBc2
and MN) might enter CD4-negative cell
lines using CXCR4. In order
to test this hypothesis, the inhibition of
CXCR4-mediated infection
of recombinant HIV-1 by CXCR4 natural ligand
SDF-1 was performed
(
3). A3, A5, and SupT1 cells were
incubated with equivalent
amounts of RT activity (25,000 cpm) of
recombinant HIV-1-CAT pseudotyped
with HXBc2 envelope glycoprotein in
the presence of different
concentrations of SDF-1, as already described
(
3). As expected,
the entry of laboratory-adapted
T-cell-tropic viruses into A3,
A5, and SupT1 cells was inhibited by
SDF-1 in a dose-dependent
fashion, as shown by the results of the CAT
assays (Fig.
3). Moreover,
the
replication of HIV-1/HXBc2 and HIV-2/ROD10 could be inhibited
by
blocking CXCR4 on A3 and A5 cells with saturating levels of
SDF-1 (data
not shown). This result indicated that the entry of
these viruses into
A3 and A5 cells could be principally mediated
by the CXCR4 molecule. In
contrast, a saturating concentration
of the 12G5 monoclonal antibody
failed to block infection by laboratory-adapted
T-cell-tropic
HIV-1/HXBc2 or HIV-2/ROD10 as shown by the determination
of p24 levels
in A3 and A5 cell supernatants (data not shown).
According to a
previous report (
30), this suggests that CXCR4
might be
differently exposed on the membranes of different cell
lines (i.e., A3
and A5 cells) or that different virus strains
could bind different
epitopes on the CXCR4 molecule.
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FIG. 3.
CAT activity in A3 and A5 cells after a preincubation of
the cells with SDF-1 at the indicated concentrations, followed by
infection with recombinant viruses. The experiment shown is
representative of three independent experiments.
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To rule out the possibility that the entry of HIV-1 into A3 and A5
cells was mediated by different forms of CXCR4 exposed
on the cellular
surface, the nucleotide sequence of CXCR4 expressed
by A3 and A5 cells
was analyzed by sequencing. No mutations were
found. This finding
suggested that the cellular phenotype responsible
for viral entry in
the absence of CD4 was independent of mutations
in the CXCR4 sequence
(data not shown). These results indicated
that laboratory-adapted
T-cell viruses use CXCR4 as a receptor
to enter A3 and A5 cells
independently of
CD4.
In this report we demonstrate that two in vitro-established
CD4
/CCR5
/CXCR4
+ pre-T-cell
lines (A3 and A5) can be infected by wild-type laboratory-adapted
T-cells-tropic HIV-1, HIV-2/ROD10, and SIV isolates in the absence
of
CD4.
Previous reports showed that gp120 binds to CXCR4 on the cell surface
without a prior CD4 interaction and that some HIV-1
and HIV-2 mutants
that are cultured in the laboratory can infect
CD4-negative cells
(
2,
12,
13,
35). Our data show that
if one uses a
replication-competent HXBc2 virus, A3 and A5 cells
are fully permissive
for HIV-1 infection as well as HIV-2 infection.
In addition, although
SIV can infect CD4
cells through CCR5 (
29), we
found that the A3 and A5 cell lines
can be infected by SIVmac239 and by
macrophage-tropic SIVmac316
even in the absence of CCR5 expression at
the cell surface
level.
Inhibition experiments using saturating doses of a specific anti-human
CD4 monoclonal antibody (Q4120) demonstrated that the
entry of
HIV-1/HXBc2, HIV-2/ROD10, SIVmac239, and SIVmac316 into
A3 and A5 cells
was independent of the CD4 molecule, making it
unlikely that low levels
of CD4 contributed to the susceptibility
of these cell clones to HIV-1,
HIV-2, or SIV infection. When A3
and A5 cells were infected with
laboratory-adapted T-cell-tropic
viruses in the presence of an
anti-CXCR4 monoclonal antibody (12G5),
no inhibitory effects on the
infection were observed. These data
are consistent with previous
reports that showed cell type and
virus strain dependency for this
monoclonal antibody (
2).
On the other hand, SDF-1, the natural ligand for CXCR4, inhibited
infection by the fully competent laboratory-adapted T-cell-tropic
HXBc2
virus as well as by HIV-2 or recombinant viruses pseudotyped
with the
envelope glycoproteins from laboratory-adapted HXBc2
or MN. This
occurred in a concentration-dependent manner, showing
that CXCR4
functions as the primary receptor and no longer needs
the CD4
molecule.
These results strongly suggest that CXCR4 could probably interact
directly with the viral envelope glycoprotein, and unlike
CD4, it could
be necessary and sufficient for viral entry. Therefore,
at least in
this case, viral entry does not require binding of
the envelope
glycoprotein directly to the primary receptor CD4
in order to promote a
conformational change for exposure of a
binding site to chemokine
receptors. Thus, in certain cases the
chemokine receptors could
represent the primary receptor, and
the use of CD4 as a receptor might
have evolved
subsequently.
Since CXCR4 expressed by A3 and A5 cells does not show any difference
in nucleotide sequence or amino acids compared to those
of wild-type
human CXCR4, there exists the possibility that CXCR4
may be modified in
a cell-type-specific manner, resulting in the
susceptibility of these
cells to HIV-1 infection. Alternatively,
CD4-independent envelope
glycoproteins could interact with an
unknown cell surface component(s)
that may be required for CXCR4-mediated
viral entry. For example, the
importance of heparan sulfate proteoglycans
on the cell surface in the
attachment of HIV-1 to target cells
has been shown (
34). In
addition, although A3 and A5 cells do
not express the CCR5 and CD4
molecules on the cell surface, they
are permissive to a recombinant
virus pseudotyped with the envelope
glycoproteins of SIVmac239 and
SIVmac316. This suggests that SIV
may use gpr1, gpr15, strl33, or other
chemokine receptors in the
absence of CD4 or that other still-unknown
molecules may be required
as cofactors and tropism determinants for
some HIV and SIV
isolates.
Conversely, no infection of A3 and A5 cells with macrophage-tropic
(ADA) as well as ELI and dualtropic (89.6) pseudotyped
viruses was
detected. We can hypothesize that, as opposed to SIV
strains, the ADA
strain is unable to use gpr15 or alternative
coreceptors on A3 and A5
cells in the absence of CD4 or that SIV
may use an unknown molecule(s)
as a
coreceptor.
CXCR4 in association with CD4 is an efficient receptor for HIV-1
isolates 89.6 and ELI (
4). Since A3 and A5 cells are
resistant
to infection by 89.6 and ELI, it is possible that different
viruses
interact with different regions of CXCR4 or that primary
strains
need a conformational change induced in their envelope
glycoproteins
by CD4 to expose a binding domain for the coreceptors
(
27).
The precise molecular ratio between CD4 and chemokine
receptors
that is necessary for a productive infection at the
single-cell
level is still unknown. It has been shown that cells
expressing
a large amount of CD4 on the membrane require only a trace
amount
of CCR5 for maximal infection by macrophage-tropic strains. In
contrast, cells with low surface expression of CD4 are more dependent
on coreceptor expression levels (
16,
21,
23).
It has been recently demonstrated that HIV Env is able to interact in a
CD4-independent manner with CXCR4 (
2,
13,
37),
although
Mondor et al. (
21) reported that the determinant in
the
interaction between the envelope glycoproteins of different
HIV-1
viruses and CXCR4 is the level of CD4 expression. Results
obtained from
these studies using soluble forms of the envelope
glycoprotein are not
fully representative of an in vivo infection
that utilizes infectious
virus. A3 and A5 are the first CD4-negative
T-cell lines permissive of
infection by wild-type HIV-1 laboratory-adapted
and SIV
isolates.
Since the A3 and A5 cell lines appear to resemble immature T cells
blocked at the earliest intrathymic T-cell differentiation
stage, they
may represent a useful model to study putative cellular
receptors that
might be present during the early phase of differentiation
of T cells.
Furthermore, studies of A3 and A5 cells may also provide
new insights
into the usage of the CXCR4 molecule by different
HIV strains. It
remains to be shown whether the CD4-independent,
CXCR4-dependent
phenotype exhibited by laboratory-adapted viruses
and the
CD4-independent phenotype exhibited by SIV isolates have
implications
for pathogenesis in
vivo.
| |
ACKNOWLEDGMENTS |
We thank J. Sodroski, R. Desrosiers, H. Choe, M. Farzan, P. Lusso,
and the Medical Research Council (MRC) for reagents, A. Amadori and
D. M. R. Negri for critical reading of the manuscript, M. Tripaldi for technical assistance, and A. Lippa and F. M. Regini for editorial assistance.
This work was supported by grants from the AIDS Project of the Ministry
of Health, Rome, Italy.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Laboratory of
Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39-06-49903321. Fax: 39-06-49387184. E-mail: borsetti{at}iss.it.
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Journal of Virology, July 2000, p. 6689-6694, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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