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Journal of Virology, January 2001, p. 1077-1082, Vol. 75, No. 2
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.2.1077-1082.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
LFA-1 Expression on Target Cells Promotes Human Immunodeficiency
Virus Type 1 Infection and Transmission
Catarina E.
Hioe,1,*
Peter C.
Chien Jr.,1
ChaFen
Lu,2
Timothy A.
Springer,2
Xiao-Hong
Wang,1
Juan
Bandres,1 and
Michael
Tuen1
New York University School of Medicine and
Manhattan VA Medical Center, New York, New York
10010,1 and The Center for Blood
Research and Harvard Medical School, Boston, Massachusetts
021152
Received 26 May 2000/Accepted 25 October 2000
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ABSTRACT |
While CD4 and the chemokine receptors are the principal receptors
for human immunodeficiency virus (HIV), other cellular proteins, such
as LFA-1, are also involved in HIV infection. LFA-1 and its ligands,
ICAM-1, ICAM-2, and ICAM-3, can be expressed on the cells infected by
HIV, as well as on the HIV virions themselves. To examine the role of
LFA-1 expressed on target cells in HIV infection, Jurkat-derived
J
2.7 T-cell lines that express either wild-type LFA-1, a
constitutively active mutant LFA-1, or no LFA-1 were used. The presence
of wild-type LFA-1 enhanced the initial processes of HIV infection, as
well as the subsequent replication and transmission from cell to cell.
In contrast, the constitutively active LFA-1 mutant failed to promote
virus replication and spread, even though this mutant could help HIV
enter cells and establish the initial infection. This study clearly
demonstrates the contribution of LFA-1 in the different stages of HIV
infection. Moreover, not only is LFA-1 expression important for initial
HIV-cell interaction, subsequent replication, and transmission, but its
activity must also be properly regulated.
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TEXT |
While the interaction of the human
immunodeficiency virus (HIV) envelope glycoprotein gp120 with CD4 and
the chemokine receptors CXCR4 and CCR5 is clearly required to initiate
HIV infection, it has now become evident that other cell membrane
proteins, including the major adhesion molecule LFA-1 (CD11a/CD18) and
its ligands ICAM-1, ICAM-2, and ICAM-3, are also involved in HIV
infection (reviewed in reference 12). These molecules are
expressed on cells that serve as hosts for the virus, as well as on the
envelopes of HIV virions. Previous studies by Fortin et al.
(6) and Rizutto and Sodroski (18)
demonstrated that ICAM-1 incorporated into the envelopes of HIV virions
increased the infectivity of the virus 2- to 10-fold. These results
suggest that ICAM-1 molecules present on the surfaces of HIV virions
are functional and capable of interacting with the LFA-1 receptor on
the target cell surface and that this interaction facilitates virus
binding to and entry into the cell.
LFA-1 and its ICAM ligands have also been shown to be necessary for
syncytium formation in HIV-infected cultures and for efficient cell-to-cell transmission of the virus. Hildreth and Orentas
(11) were the first to show that antibodies to LFA-1
inhibited syncytium formation induced by HIV. This finding was
corroborated by other investigators who showed that syncytium formation
in HIV-infected cultures was blocked by antibodies to the three ICAM
ligands (2). The LFA-1/ICAM-1 interaction was also found
to be important for conjugation between HIV-infected dendritic cells
and CD4+ T cells in the absence of any syncytium formation
(20). Blocking such interactions by monoclonal antibodies
(MAbs) to LFA-1 or ICAM-1 reduced virus transfer from the dendritic
cells to the T cells. Most recently, a dendritic-cell-specific C-type
lectin, DC-SIGN, which binds ICAM-3 with high affinity, has been shown to play a role in promoting the capture of HIV type 1 (HIV-1) by
dendritic cells and facilitating the transmission of the virus to
CD4+ T cells (8, 9).
LFA-1 is also known to affect HIV neutralization by virus-specific
antibodies. Gomez and Hildreth (10) and Hioe et al.
(13) demonstrated that HIV neutralization by HIV-positive
plasma or by anti-gp120 MAbs was enhanced in the presence of MAbs to
LFA-1. Hioe et al. (13) further showed that enhanced
neutralization was observed when the anti-LFA-1 MAbs were present only
during the initial 24 h of virus infection or were added 24 h
postinfection. These results suggest that the anti-LFA-1 MAbs could act
on different stages of HIV-1 infection, including the initial
virus-cell interaction as well as the replication and spread of the
virus from cell to cell.
Although previous studies have indicated that LFA-1 and its ICAM
ligands are involved in multiple stages of HIV infection, little work
has been done to determine to what extent the expression and activation
state of LFA-1 on cells targeted by HIV affect virus infection and
transmission. HIV-1 virions bearing ICAM-1 were more infectious than
their ICAM-1-negative counterparts (6, 18); however, this
observation is relevant only if the cells targeted by the virus express
LFA-1 capable of binding ICAM-1. Moreover, the binding of LFA-1 to
ICAM-1 requires activation of LFA-1: upon cellular stimulation by
cross-linking of CD3, CD2, major histocompatibility complex class II
molecules, or chemokine receptors, or by activation of protein kinase C
with phorbol ester, LFA-1 undergoes a rapid and reversible conversion
from a low- to a high-avidity state. Expression of the activated form
of LFA-1 on T-cell lines was shown to render the cells more susceptible to infection by HIV (4). Increased susceptibility to HIV
was also observed with peripheral blood mononuclear cells and T-cell lines treated with antibodies that activate LFA-1 (7).
Hence, LFA-1 expression and its activation state could significantly affect the susceptibility of cells to HIV infection and may influence the types of cells in which virus infection is established and to which
it spreads.
In the present study we systematically examined the effects of LFA-1
expression and activation state on HIV infection and transmission by
using human T-cell lines that differed one from another only by the
expression and type of LFA-1 present on their cell surfaces. We used
CD4+ J2.7 T cells that lacked LFA-1 or had been
transfected to express wild-type or mutant LFA-1. The generation and
characterization of these cell lines were reported previously
(15, 21, 22). Briefly, the J2.7 cells were generated
from Jurkat cells which had been treated with ethyl methanesulfonate
and were selected for complete loss of cell surface LFA-1. The absence
of LFA-1 expression was shown to be due to the absence of the LFA-1 
chain (CD11a or L). Thus, when the cells were
transfected with cDNA of the wild-type subunit, cell surface
expression of LFA-1 was restored; these cells were designated
J2.7/LFA-1 wt. In addition, a J2.7 cell line expressing a
constitutively active LFA-1 deletion mutant was generated
(J2.7/LFA-1 
). The LFA-1 deletion mutation was produced by
deleting the conserved GFFKR sequence in the membrane-proximal cytoplasmic domain of the LFA-1 subunit. In contrast to the wild-type LFA-1, which requires cellular activation for high-affinity binding to ICAM-1, the GFFKR deletion mutant binds ICAM-1
constitutively and is locked in the highly adhesive state
(15). For this study, clones of J2.7/LFA-1 wt (clone 8)
and J2.7/LFA-1 (clone 22) were used; their LFA-1 expression has
been studied in detail and has previously been described
(15). For comparison, the J2.7 cells transfected with
the vector alone were also produced (J2.7/mock); these cells
expressed no LFA-1 on the surface. The expression levels of other
membrane proteins, including CD4, CXCR4, ICAM-1, ICAM-2, and ICAM-3, on
the three J2.7 transfectants were comparable (data not shown). These
Jurkat-derived J2.7 cells do not express the CCR5 receptors. These
cell lines were cultured in RPMI 1640 supplemented with 20% fetal
bovine serum, L-glutamine, and 3 µg of puromycin per ml.
Effect of LFA-1 expression on the initial events of HIV
infection.
With these J2.7 transfectants, the presence and
activation state of LFA-1 on the surfaces of cells infected with HIV
were studied to determine whether they had any effect on the initial events of virus infection, including virus attachment to the cells, entry into the cells, and integration. To address this question, we
compared the amounts of virus that entered and initiated infection in
the three J2.7 cell lines after 18 h of exposure to the virus. The level of HIV-1 DNA associated with each cell line was determined by
PCR and Southern blotting as described previously (1).
Since J2.7 cells express CXCR4 but not CCR5 receptors, infection by a clade B X4R5-tropic HIV-1 isolate, SF33, and an X4-tropic HIV-1 laboratory strain, IIIB, was examined in the study. These viruses were
grown in J2.7/LFA-1 wt cells and expressed the ICAM ligands (data
not shown). The same amount of cell-free virus supernatant (4.5 µg of
p24 for SF33 or 3.3 µg of p24 for IIIB) was used to infect the three
J2.7 cell lines (4 × 106 cells/ml). After 18 h of infection, HIV-1 DNA was amplified from cell lysates (from an
equivalent of 105 cells) using Gag-specific primers SK38
and SK39 with GeneAmplimer HIV-1 control reagents (Perkin-Elmer) to
produce a 115-bp HIV-1 Gag fragment. PCR products were transferred to a
nylon membrane, hybridized with internal probe SK19, and detected with
a chemiluminescent digoxigenin system (Boehringer Mannheim). To
normalize the amount of cellular DNA analyzed, -actin DNA was also
amplified from the same lysates.
The results show that more abundant HIV DNA was found in SF33-infected
J2.7/LFA-1 wt than in J2.7/mock cells, while the amount of HIV
DNA associated with SF33-infected J2.7/LFA-1 cells was similar
to that in J2.7/LFA-1 wt cells infected with the same virus (Fig.
1A). In contrast, comparable amounts of
-actin DNA were detected in the three cell lines. This pattern was
also observed with IIIB-infected J2.7 cells. To assess the results more precisely, we performed another experiment to measure the amount
of HIV DNA in the IIIB-infected J2.7 cell lysate that was diluted
1:25, 1:50, and 1:100 (Fig. 1B). Again, IIIB-infected J2.7/mock
cells were found to contain the least virus DNA. However, it was now
apparent that J2.7/LFA-1 cells contained more HIV DNA than
J2.7/LFA-1 wt cells. These results indicate that cells expressing
LFA-1, either wild type or deletion mutant, were more readily infected
with HIV than cells expressing no LFA-1, and the presence of
constitutively active LFA-1 with high affinity for ICAM-1 appeared to
further promote virus entry and infection. In consideration of the
semiquantitative nature of the PCR and Southern blot techniques used in
this study, we performed each experiment presented here at least twice,
and indeed the same results were observed consistently in the repeated
experiments; i.e., cells bearing constitutively active LFA-1 contained
the most HIV DNA, while the LFA-1-negative cells contained the least.
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FIG. 1.
Virus DNA detected in J2.7/mock, J2.7/LFA-1 wt,
and J2.7/LFA-1 cells following 18 h of infection with SF33
or IIIB. These viruses were originally produced in J2.7/LFA-1 wt
cells. (A) PCR and Southern blotting were performed using HIV-1 Gag or
-actin primers on undiluted cell lysates from an equivalent of
105 cells. Positive controls (+) for both HIV Gag and
-actin were included in each experiment. (B) In a separate
experiment, HIV-1 Gag DNA was amplified from diluted lysates of
IIIB-infected J2.7 cells. An HIV-1 Gag control (+) from the 8E5 cell
line containing a single copy of proviral HIV per cell was also tested
in the experiment.
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To confirm that the enhanced virus infection seen in cells expressing
LFA-1 was mediated by the interaction of LFA-1 on the
cells with its
ICAM ligands on the virus, HIV-1 bearing no ICAMs
was prepared by
transfecting an X4-tropic, infectious molecular
clone of
HIV-1
IIIB, R7-GFP, into human embryonic kidney 293T cells,
which express no ICAMs and have been shown to produce a relatively
high
titer of cell-free virus (
6). After 18 h of infection
with this ICAM-negative virus (0.5 µg of p24 per 10
6
cells), similar levels of virus DNA were detected in the J
2.7
cells
expressing wild-type, mutant, or no LFA-1 (Fig.
2). Thus,
LFA-1-expressing J
2.7 cells
exhibited enhanced susceptibility
to ICAM-bearing HIV but not to
ICAM-negative virus. These results
clearly demonstrate the specific
contribution of the LFA-1/ICAM
interaction in facilitating HIV
infection.
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FIG. 2.
Virus DNA detected in J2.7/mock, J2.7/LFA-1 wt,
and J2.7/LFA-1 cells following 18 h of infection with HIV-1
bearing no ICAMs. This virus was produced by transfecting ICAM-negative
293T cells with an infectious HIV-1 clone, R7-GFP. PCR and Southern
blotting were performed with HIV-1 Gag primers on cell lysates from an
equivalent of 105 cells. Positive (8E5 cells) and negative
controls for HIV Gag were also included in this experiment.
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HIV replication in J2.7 cells expressing wild-type, mutant, or
no LFA-1.
Next, we investigated the kinetics of p24 antigen
production as a measure of the virus replication rate in the three
J2.7 transfectants infected with SF33 or IIIB. For these
experiments, each of the three J2.7 cell lines was incubated for
24 h at 37°C with the same amount of virus supernatant (1 µg
of p24 for SF33 or 0.8 µg of p24 for IIIB per 106 cells),
washed, and then cultured for up to 3 weeks. Cells were collected every
2 or 3 days and treated with 1% Triton X-100 (100 µl/106
cells), and the amount of p24 in the cells was measured by a noncommercial enzyme-linked immunosorbent assay. As shown in Fig. 3 (top), the level of p24 production in
SF33-infected J2.7/mock cells was much lower than in J2.7/LFA-1
wt cells infected with the same virus. In J2.7/mock cells, the p24
concentration reached its peak on day 9 at 840 ng/ml, whereas in
J2.7/LFA-1 wt cells, as much as 2,200 ng of p24 per ml was produced
on day 9 postinfection. Overall, p24 production in J2.7/LFA-1 cells was also lower than in J2.7/LFA-1 wt cells, even though
initially the p24 levels in these two cell lines were comparable. A
more striking difference in the kinetics of p24 production was observed
in IIIB-infected J2.7 cells (Fig. 3, bottom). The p24 level reached
its maximum at 1,400 ng/ml on day 9 in IIIB-infected J2.7/LFA-1 wt
cells. In contrast, only 500 ng of p24 per ml was produced in
J2.7/LFA-1 cells on day 9. In IIIB-infected J2.7/mock cells,
both the rate and level of p24 production were also much lower: it took 16 days of infection to achieve a maximal p24 level of 800 ng/ml. These
results, taken together with the data in Fig. 1, indicate that the
presence of LFA-1 on target cells, particularly the wild-type form,
promotes HIV entry and replication in the cells. The constitutively active LFA-1 deletion mutant also enhances the initial events of HIV
infection but seems to retard the subsequent process(es) (see below).
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FIG. 3.
Virus replication in J2.7 transfectants expressing
wild-type, mutant, or no LFA-1. J2.7 cells were infected with SF33
or IIIB, and p24 production in 2 × 106 cells was
measured by enzyme-linked immunosorbent assay over time.
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Effect of LFA-1 on virus spread in J2.7 cultures.
The
higher level of p24 found in HIV-infected J2.7/LFA-1 wt cells might
be a reflection of a higher number of infected cells present in the
J2.7/LFA-1 wt culture as a result of a more efficient spread of the
virus from cell to cell in the culture. In contrast, virus spread to
cells with no LFA-1 or with the LFA-1 deletion mutant might be less
efficient, and thus, fewer infected cells would be present in the
infected J2.7/mock and J2.7/LFA-1 cultures. To test this
hypothesis, we quantitated the infected cells over time in the three
J2.7 cultures following infection with SF33 or IIIB virus.
Virus-infected cells were detected by intracellular anti-p24 antibody
staining and were analyzed by flow cytometry. J2.7 cells were
infected with SF33 or IIIB as described above for Fig. 3 and sampled
periodically for staining with the fluorescent RD1-labeled anti-p24 MAb
KC57 (Immunotech). Cells stained with an RD1-labeled isotype
immunoglobulin control were used to establish background fluorescence.
The results presented in Fig. 4 (top)
demonstrate that the percentage of SF33-infected cells in the
LFA-1-negative J2.7/mock culture increased slowly and attained a
maximum of 19% on day 16. In contrast, in the J2.7/LFA-1 wt culture
infected with the same virus, 27% of the cells were positive as early
as day 9. In the J2.7/LFA-1 culture, the number of infected
cells rose rapidly during the first week but reached a plateau on day 9 at only 19%. A similar pattern was obtained when we compared the
number of virus-infected cells in the three J2.7 cultures exposed to
IIIB (Fig. 4, bottom). For controls, uninfected J2.7 cells were
stained with RD1-labeled KC57, and <0.7% positive cells were detected
in each experiment (data not shown). These data clearly indicate that
the number of infected cells increased more rapidly and reached a
higher level in the J2.7/LFA-1 wt culture than in the J2.7/mock
or J2.7/LFA-1 cultures infected with the same virus. We also
observed that the mean fluorescence intensity of the infected cells,
while changing over time, was not significantly different among the three J2.7 cultures (data not shown), indicating that the amounts of
p24 produced per cell were similar whether the cells expressed wild-type, mutant, or no LFA-1. These findings are consistent with the
general pattern of p24 production seen in Fig. 3 and support the idea
that the rate of virus spread in cells expressing wild-type LFA-1 is
substantially greater than in the cells with the LFA-1 deletion mutant
or with no LFA-1.
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FIG. 4.
Number of infected cells in J2.7/mock, J2.7/LFA-1
wt, and J2.7/LFA-1 cultures following infection with SF33 or
IIIB. Infected cells were detected by intracellular p24 staining and
quantitated by flow cytometry.
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It should be noted, however, that the different numbers of infected
cells observed in Fig.
4 could reflect not only distinct
rates of virus
spread in the three cell lines but also the number
of cells initially
infected upon exposure to the virus (Fig.
1).
To measure more
specifically the efficiency of virus spread in
the infected J
2.7
cultures, we performed experiments in which
uninfected J
2.7/LFA-1
wt, J
2.7/LFA-1
, or J
2.7/mock cells
were each inoculated with
a fixed number of SF33-infected J
2.7/LFA-1
wt cells, so that 7% of
infected J
2.7/LFA-1 wt cells were present
initially in each of the
mixed cultures (i.e., the ratio of infected
to uninfected cells at the
beginning of the culture was 7 to 100).
We then compared the increase
in the number of infected cells
in each culture as the virus spread
from SF33-infected J
2.7/LFA-1
wt cells to the uninfected J
2.7
cells with either wild-type,
deletion mutant, or no LFA-1. The results
show that the SF33 virus
spread to J
2.7/LFA-1 wt cells more readily
than to either J
2.7/mock
or J
2.7/LFA-1
cells (Fig.
5). Notably, the levels of virus
transmission to J
2.7/LFA-1
and to J
2.7/mock cells were
similar,
indicating that the LFA-1 deletion mutant, in contrast to the
wild-type LFA-1, did not facilitate HIV spread in the J
2.7 cultures,
even though this constitutively active LFA-1 enhanced the initial
infection by cell-free virus.
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FIG. 5.
Comparison of virus spread to J2.7 target cells
expressing wild-type, mutant, or no LFA-1. Each J2.7 cell line was
mixed with SF33-infected J2.7/wt cells at a ratio of 100 to 7. Infected cells were detected by intracellular fluorescence staining
with an anti-p24 MAb and measured over time by flow cytometry.
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This study provides direct evidence that adhesion molecule LFA-1
expressed on the surfaces of cells targeted by HIV plays
a significant
role in promoting the initial stages of HIV infection.
Thus, cells
expressing LFA-1 are more prone to HIV infection than
cells without
LFA-1. The results complement previous findings
which showed that the
presence of ICAM-1 on the envelopes of HIV
virions rendered the virus
more infectious. Taken together, these
studies support the hypothesis
that LFA-1 on the target cells
interacts with the ICAM ligands on the
HIV virion; such an interaction
facilitates virus binding to the cells
and enhances the rate of
virus entry and infection, presumably by
helping to overcome the
repulsive forces present between the negatively
charged gp120
on the virion surface and the negatively charged cell
membrane
(
3). In agreement with this notion, we observed
that HIV infection
was increased even more when the target cells
expressed the mutant
form of LFA-1 that constitutively retains a high
adhesiveness
for its ICAM ligands. Similar results were reported
previously
with a different human T-cell line (HPB-ALL) that was
chemically
mutated to express the constitutively active form of LFA-1
(
4)
and with peripheral blood mononuclear cells or T-cell
lines treated
with anti-LFA-1 antibodies that activate LFA-1 and
convert it
to a high adhesive form (
7). Hence, a
high-affinity LFA-1/ICAM-1
interaction is indeed beneficial for HIV's
initial attachment
to and entry into the target
cells.
In contrast to the requirement for virus-cell attachment, we
demonstrated here for the first time that to promote efficient
cell-to-cell spread of HIV, the presence of activated and highly
avid
LFA-1 on the cell surface is not sufficient; rather, properly
functional LFA-1 that can regulate its adhesiveness is required.
We
observed that the presence of the constitutively active LFA-1
deletion
mutant on target cells did not promote virus replication
and spread as
seen with wild-type LFA-1, even though this LFA-1
deletion mutant
helped establish the initial virus infection.
It should also be noted
that the cells expressing the LFA-1 deletion
mutant tend to grow in
tight clusters with most cells in close
contact with neighboring cells,
but virus spread was not accelerated
in these cells. Although the
reason for this phenomenon is not
fully understood, these findings
suggest at least three possible
explanations. First, LFA-1 expression
on HIV-infected cultures
promotes syncytium formation
(
11), and in the cells with constitutively
active LFA-1,
rapid syncytium formation and death of the fused
cells may cause the
virus production to drop off faster. Second,
the high affinity between
the virus and the constitutively active
LFA-1 on the cells may hinder
the cell-to-cell transfer of progeny
virus. Previous studies by Weber
et al. (
21) revealed that J
2.7/LFA-1
cells could
not modulate cell-cell adhesiveness and failed to
undergo
transendothelial migration in response to chemokines.
Similarly, virus
particles produced in cells with the LFA-1 deletion
mutant may adhere
too tightly to the host cells and may not spread
to other cells in the
culture efficiently. In support of this
idea, we observed, using the
MAb-mediated virus capture assay,
that virions produced in
J
2.7/LFA-1
cells incorporated into
their envelopes a high level
of LFA-1, while virions from J
2.7/LFA-1
wt cells acquired much fewer
LFA-1 molecules (data not shown).
Although it remains unclear whether
the LFA-1 deletion molecules
acquired by the HIV virions from the
J
2.7/LFA-1
cells retained
their highly adhesive state, the
presence of such highly avid
LFA-1 could potentially prevent the
budding and detachment of
virus progeny from the host cells. Third, the
deletion in the
cytoplasmic domain of the
chain of the LFA-1
deletion mutant
may affect the intracellular signaling and cytoskeleton
rearrangement
involved in the HIV maturation and/or budding process
(
14,
16,
17,
19). As a result, fewer mature virions may be
produced
in LFA-1 deletion mutant-expressing cells than in the cells
expressing
wild-type LFA-1. Overall, the data from this study clearly
show
that the expression of functional LFA-1 with well-regulated
adhesiveness
on cells targeted by HIV significantly promotes HIV
infection
and
transmission.
LFA-1 is expressed in vivo on various types of leukocytes, including
lymphocytes, monocytes, and dendritic cells, that can
be infected by
HIV. In response to antigens, chemokines, and other
inflammatory
stimuli, LFA-1 on these cells becomes activated and
capable of binding
its ICAM ligands with high affinity. Our findings
suggest that these
stimulated cells would be more susceptible
to HIV and could be the
preferred targets for the virus. Thus,
the presence of such cells in
the mucosa at the site of HIV entry,
for example, may allow the virus
to more readily establish the
initial infection. Subsequently, as
indicated by this and other
studies (
11,
13,
20), virus
spread from infected cells to
uninfected cells is also enhanced by the
presence of LFA-1 on
the cell surface. Furthermore, LFA-1 expression
may have a greater
impact on HIV infectivity when gp120 density on the
virus is low,
either due to shedding or because those gp120 molecules
are concealed
by antibodies. A number of studies have shown previously
that
LFA-1/ICAM-1 interaction between the virus and target cells
reduces
the effectiveness of anti-HIV antibodies in neutralizing the
virus
(
5,
10,
13). Therefore, LFA-1 and other adhesion
molecules
present on the cell surface and on the HIV virions are
important
determinants in HIV pathogenesis, affecting virus infectivity
and transmission as well as virus neutralization by
antibodies.
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ACKNOWLEDGMENTS |
We thank Susan Zolla-Pazner for support and assistance throughout
this project and for helpful comments on the manuscript.
The work was supported by a developmental research grant from the
Center for AIDS Research of the New York University Medical Center
(C.E.H.), by a Merit Review Entry Program Award (C.E.H.), and by NIH
grants HL-59725 and AI-32424 (Susan Zolla-Pazner).
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FOOTNOTES |
*
Corresponding author. Mailing address: VA Medical
Center
Research Service, 423 E. 23rd St., Room 18-124 North, New York,
NY 10010. Phone: (212) 263-6769. Fax: (212) 951-6321. E-mail:
hioec01{at}med.nyu.edu.
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Journal of Virology, January 2001, p. 1077-1082, Vol. 75, No. 2
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.2.1077-1082.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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