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J Virol, March 1998, p. 2105-2112, Vol. 72, No. 3
Centre de Recherche en Infectiologie, Centre
Hospitalier Universitaire de Québec, Pavillon CHUL, and
Département de Microbiologie, Faculté de Médecine,
Université Laval, Ste-Foy, Québec, Canada G1V 4G2
Received 13 October 1997/Accepted 6 December 1997
The incorporation of host-derived proteins in nascent human
immunodeficiency virus type 1 (HIV-1) particles is a
well-established phenomenon. We recently demonstrated that the physical
presence of host-encoded ICAM-1 glycoproteins on HIV-1 leads to a
significant increase in virus infectivity in an ICAM-1/LFA-1-dependent
fashion (J.-F. Fortin, R. Cantin, G. Lamontagne, and M. Tremblay,
J. Virol. 71:3588-3596, 1997). We show here that conversion of
LFA-1 to high affinity for ICAM-1 with the use of anti-LFA-1 antibodies (clones NKI-L16 and MEM83) markedly enhances the susceptibility of
different target T-lymphoid cell lines, as well as of primary peripheral blood mononuclear cells, to infection by ICAM-1-bearing HIV-1 particles (6- to 95-fold). It is known that T-cell receptor (TCR)
cross-linking induces a transient increase in LFA-1 affinity for
ICAM-1. Treatment of peripheral blood mononuclear cells with anti-TCR
antibodies (clone OKT3) resulted in a transient increase in
susceptibility to infection by ICAM-1-positive virions that parallels
the previously reported kinetics of the LFA-1/ICAM-1 adhesion
mechanism. Our results led us to postulate that the strong interaction
taking place between virally incorporated ICAM-1 and cell
surface-activated LFA-1 markedly enhances the efficiency of virus
binding and entry, thus favoring greater infection by ICAM-1-bearing
HIV-1 particles. In view of the knowledge that primary HIV-1 isolates
harbor host-derived ICAM-1 on their surfaces, these results provide new
information about the role of host-derived ICAM-1 in the life cycle of
HIV-1 and how it could positively modulate the dynamics of the viral
infection, mainly in cellular compartments, such as the lymphoid
tissues, where the level of cellular activation is high and where the
probability of encountering a T cell expressing the activated LFA-1
form is also elevated.
In vivo, CD4+ T
lymphocytes and monocytes-macrophages constitute the main reservoirs
for the production and maintenance of human immunodeficiency virus type
1 (HIV-1) (48, 54). Infection of these cells occurs
following the high-affinity interaction between the viral surface gp120
and the cell surface CD4 molecule (15). However, in order
for the fusion to occur, the sole interaction between gp120 and CD4 is
not sufficient (40), and the involvement of other
molecules is required. These other cellular components, the so-called
coreceptors, have been recently identified and characterized. Formerly called LESTR/HUMSTR/fusin, the chemokine receptor CXCR4 has
been shown to act as the coreceptor for T-cell-tropic strains of HIV-1
(22). For macrophage-tropic HIV-1 isolates, the CCR5 molecule has been identified as the major coreceptor (16,
19), even though CCR3 and CCR2b are also used, but to a lesser
extent (14, 18). Following ligation of gp120 with CD4, a
high-affinity binding site for the chemokine receptor is created, thus
leading to membrane fusion and virus entry (36, 58, 59).
Besides these essential elements for viral entry, other cellular
molecules could play important, although accessory, roles during the
process of virus uptake.
It has been known for a while that HIV-1 can incorporate, besides its
surface glycoproteins, a vast array of cell membrane molecules while
budding out from the infected cell. For example, major
histocompatibility complex class II (MHC-II) DR molecules were the
first host constituents found embedded within HIV-1 particles and these
were identified as a potential source of false-positive reactions in
enzymatic screening tests (31). Many other cellular structures were found to be acquired by newly formed HIV-1, such as
HLA-DP and -DQ, Recently, several studies investigated the functionality of
host-derived molecules when present on the virion surface. The first,
although indirect, evidence of the functionality of virally incorporated adhesion molecules came from the demonstration that anti-LFA-1 antibodies can act synergistically with antiserum to neutralize HIV-1 particles (28). More direct proof was
provided by the demonstration that an increase in virion-incorporated
HLA-DR and ICAM-1 resulted in enhanced infectivity toward CD4-negative cell lines (12). Saiffudin et al. demonstrated that CD55 and CD59, two glycosylphosphatidylinositol-linked complement control proteins, can protect HIV-1 from complement-mediated virolysis when
incorporated into budding virions (52), while
virion-incorporated host MHC-II molecules were shown to present
bacterial superantigens (50). We have been able to
demonstrate, by using mutagenized cell lines, that incorporation of
MHC-II molecules within the viral envelope enhances the process of
viral infection (9). Recently, we developed a
transient-transfection-and-expression system that permits the
production of virions differing only by the absence or the presence of
a specific cell surface molecule on their surfaces. By using this new
technical approach, we found that acquisition of cellular HLA-DR1
molecules by budding HIV-1 is associated with a 1.6- to 2.5-fold
increase in virus infectivity (10). Moreover, we have shown
that incorporation of host-derived ICAM-1 by progeny viruses leads to a
5- to 10-fold increase in HIV-1 infectivity, caused by an interaction
between virally incorporated ICAM-1 and cell surface LFA-1
(23), an observation which has been corroborated by another
group (49). This finding has great clinical relevance,
considering that ICAM-1 is acquired by clinical HIV-1 isolates grown on
primary mononuclear cells (4, 11, 24) and the in vivo
HIV-1-producing cells are activated CD4+ T cells and
macrophages, cells which are both known to express high levels of
ICAM-1 (55). Therefore, it is likely that HIV-1 isolates
found in vivo carry on their surfaces host-derived ICAM-1 glycoproteins.
The counterreceptor for ICAM-1 is LFA-1, a member of the integrin
family that is expressed mainly on lymphocytes, granulocytes, monocytes, and macrophages, with elevated levels on memory T cells (53). The activation of leukocytes with various agents like phorbol esters and chemoattractant, or cross-linking of specific surface receptors such as the T-cell receptor (TCR)/CD3 complex, CD2,
and MHC-II, induces LFA-1-mediated binding to ICAM-1 (17). This transient change in ICAM-1 binding is thought to involve both a
variation in the affinity of LFA-1 for ICAM-1 caused by a
conformational change and an increase in avidity mediated by clustering
of the molecules (20). This dynamic regulation of integrins
allows the cells that bear these molecules to convert rapidly from a
nonadherent to an adherent phenotype and vice versa. Since
LFA-1 can be expressed in two different conformational states, i.e.,
low versus high affinity for ICAM-1, we therefore examined whether the
activation state of LFA-1 on the target cell surface could affect the
overall susceptibility to infection by ICAM-1-bearing HIV-1 particles.
Cells.
The 1G5 T-cell line, a Jurkat E6.1 derivative that
harbors two stably integrated constructs consisting of the luciferase
gene under the control of the HIV-1SF2 long terminal repeat
(LTR) and Jurkat-tat, Sup-T1, and PM1 cells were obtained
through the AIDS Research and Reference Reagent Program (Division of
AIDS, National Institute of Allergy and Infectious Diseases), while
293T cells were kindly provided by W. C. Greene (The J. Gladstone
Institutes, San Francisco, Calif.). Primary peripheral blood
mononuclear cells (PBMCs) from healthy donors were isolated by
Ficoll-Hypaque density gradient centrifugation and cultured in the
presence of phytohemagglutinin P (PHA-P; Sigma, St. Louis, Mo.) at 3 µg/ml and recombinant human interleukin-2 at 30 U/ml for 3 days at
37°C in a 5% CO2 atmosphere prior to viral infection.
Plasmids.
pNL4-3 is a full-length infectious molecular clone
of HIV-1 (2). Proviral plasmid pHXB-Luc was originally
derived from pHXB-2D, in which a part of the nef gene was
deleted and replaced with the luciferase reporter gene (13).
This infectious molecular clone of HIV-1 was kindly provided by David
Baltimore (Massachusetts Institute of Technology, Cambridge, Mass.).
pCD1.8 is a eukaryotic expression vector containing the entire human
ICAM-1 cDNA and was obtained from Timothy A. Springer (The Center for
Blood Research, Boston, Mass.) (56).
Antibodies.
Anti-ICAM-1 (anti-CD54) antibody RR1/1.1.1 was
kindly provided by Robert Rothlein (Boehringer Ingelheim, Ridgefield,
Conn.) (51). NKI-L16 (anti-CD11a) was obtained from
Carl C. Figdor (University Hospital Nijmegen, Nijmegen, The
Netherlands) (34), while MEM30 and MEM83 (anti-CD11a) were
kind gifts from Vaclav Horejsi (Institute of Molecular Genetics,
Prague, Czech Republic) (5).
Production of virus stocks.
Viral particles differing only
by the presence or the absence of the ICAM-1 molecule in their envelope
were produced by CaPO4 transfection in 293T cells as
described previously (23). Cotransfection of pNL4-3 or
pHXB-Luc with pCD1.8 led to the production of virus stocks called
ICAM-1/POS because such virions bear host-derived ICAM-1. Transfection
of 293T cells with pNL4-3 or pHXB-Luc only resulted in the production
of virus preparations named ICAM-1/NEG, since cellular ICAM-1
glycoproteins are not found embedded within such virions. Indeed,
ultracentrifuged virus preparations harvested from 293T cells
transiently transfected only with a molecular clone of HIV-1 are
negative for ICAM-1 as monitored by an enzymatic assay (data not
shown). Virus stocks were normalized for virion content by using a
commercial assay for viral major core protein p24 (Organon Teknika,
Durham, N.C.).
Virus infection.
Cells were first either left untreated or
treated for 30 min at 37°C with anti-LFA-1 monoclonal antibody MEM30
(10 µg/ml), MEM83 (3 µg/ml), or NKI-L16 (1 µg/ml). These
concentrations have been reported to either block (MEM30)
(5) or activate (MEM83 and NKI-L16) LFA-1 (34,
35). Viral stocks were also left untreated or treated for 30 min
at 37°C with anti-ICAM-1 monoclonal antibody RR1/1.1.1 (20 µg/ml).
For the kinetic experiments, PBMCs were first incubated for 30 min on
ice with OKT3 (2 µg/ml) before incubation at 37°C for the times
indicated in Results with goat anti-mouse immunoglobulins (5 µg/ml).
Infections were done with the amount of virus (standardized in term of
p24 protein) necessary to infect 105 cells (1.5 ng of p24
for Jurkat-tat cells or 10 ng of p24 for other lymphoid cell
lines and PBMCs). Infections were allowed to proceed for 90 min at
37°C. The cells were next washed twice with phosphate-buffered
saline, resuspended in 200 µl of RPMI culture medium (supplemented
with recombinant human interleukin-2 at 30 U/ml for PBMCs), and
transferred to a 96-well flat-bottom tissue culture plate (Microtest
III, Falcon, Becton Dickinson, Lincoln Park, N.J.). After a 24-h
incubation period, a combination of 1 µM azidothymidine
(3'-azido-2',3'-dideoxythimidine) and 30 µM didanosine
(2',3'-dideoxyinosine) was added to abrogate any reinfection events.
Finally, HIV-1-infected cells were incubated for an additional 24-h
period (1G5 and Jurkat-tat cells) or 48 h (PBMCs and
Sup-T1, PM1, and Jurkat E6.1 cells) at 37°C. After this final
incubation, cells were lysed and luciferase activity was monitored as
described previously (10, 23).
LFA-1 activation on 1G5 T-lymphoid cells increases susceptibility
to infection by ICAM-1-positive HIV-1 particles.
To test the
hypothesis that LFA-1 activation on 1G5 T-lymphoid cells increases
susceptibility to infection by ICAM-1-positive HIV-1 particles, we
first inoculated 1G5 cells with virus stocks harvested from transiently
transfected 293T cells as described previously (23). It
should be noted that 1G5 is a clone of Jurkat E6.1 cells stably
transfected with two copies of a construct consisting of the luciferase
reporter gene placed under the control of the HIV-1 LTR (3).
Upon virus infection, these cells express luciferase due to the viral
Tat-mediated transactivation of the HIV-1 LTR. We then tested if
antibody-mediated modification of the LFA-1 conformation could affect
the susceptibility of 1G5 cells to infection by ICAM-1-free
(ICAM-1/NEG) and ICAM-1-bearing (ICAM-1/POS) HIV-1 particles. This was
achieved by pretreating or not pretreating 1G5 cells with MEM83 and
NKI-L16, two anti-LFA-1 antibodies known to induce the switching of
LFA-1 from low to high affinity for ICAM-1 (34, 35). Other
experimental conditions consisted of virus preparations and target
cells pretreated with RR1/1.1.1 (anti-ICAM-1) and MEM30 (anti-LFA-1),
respectively, two antibodies known to abolish the ICAM-1/LFA-1
interaction (5, 41). For each condition, cells were infected
with HIV-1NL4-3 ICAM-1/NEG and ICAM-1/POS preparations that
were normalized according to p24 content. As measured by luciferase
activity and in agreement with our previous study (23),
ICAM-1-bearing viruses are more infectious (four times) than their
ICAM-1-devoid counterparts (Fig. 1). The
observation that addition of RR1/1.1.1 and MEM30 eliminates the
enhancement of virus infectivity for ICAM-1-bearing particles is clear
evidence of the role played by the physical interaction between
virion-bound ICAM-1 and surface LFA-1 in enhancing the process of viral
infection. Most strikingly, 1G5 cells are 41 to 64 times more
susceptible to infection by ICAM-1/POS HIV-1NL4-3 particles
than to infection by ICAM-1-negative virions when the cells are first
pretreated with LFA-1-activating antibodies MEM83 and NKI-L16,
respectively.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
T Cells Expressing Activated LFA-1 Are More Susceptible to
Infection with Human Immunodeficiency Virus Type 1 Particles
Bearing Host-Encoded ICAM-1
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
2-microglobulin, CD44, CD55, and CD59,
as well as LFA-1 and ICAM-1 adhesion molecules (6, 11, 12, 21, 29,
33, 52). It has also been suggested that the profile of
virion-bound cellular constituents could be used as a marker to
identify the virus-producing cell (1).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
View larger version (28K):
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FIG. 1.
Effect of two LFA-1-activating antibodies on infection
of 1G5 cells by ICAM-1/NEG and ICAM-1/POS virions. 1G5 cells were
either left untreated or treated with various antibodies for 30 min at
37°C and then infected with ICAM-1/NEG or ICAM-1/POS
HIV-1NL4-3 particles previously treated or not treated with
ICAM-1-blocking antibody RR1/1.1.1. Cells were lysed 48 h later,
and infection was evaluated by measuring the luciferase activity
in the lysates. The results shown are means ± standard
deviations of triplicate samples and are representative of three
independent experiments. The fold increase over infection with
ICAM-1-negative virus particles is indicated for each experimental
condition. Luciferase activity in mock-infected cells was always less
than 50 × 103 cpm.
Higher susceptibility to infection by ICAM-1-bearing HIV-1 conferred by the activated form of LFA-1 is seen in several T-lymphoid cell lines. We next wanted to eliminate any cell type-specific phenomenon by using a more versatile system that is based on infection with recombinant luciferase-encoding HIV-1 particles. HXB-Luc virus particles bearing or not bearing host-encoded ICAM-1 on their surfaces were produced by transient transfection of 293T cells as described previously (10), and these virions were used to infect three different cell lines (Sup-T1, Jurkat-tat, and PM1). The authenticity of the phenomenon was proven by the fact that these cell lines were 6- to 95-fold more susceptible to infection by ICAM-1-bearing viruses than to infection by ICAM-1-free HXB-Luc particles when they were pretreated with LFA-1-activating antibodies (Fig. 2). The infection process with ICAM-1/NEG HXB-Luc particles was still unaffected by the treatment of target cells with LFA-1-activating antibodies. The LFA-1- and ICAM-1-blocking antibodies were again able to eliminate the infectivity advantage conferred by the presence on HIV-1 of host-encoded ICAM-1.
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Enhanced susceptibility to infection by ICAM-1-bearing HIV-1 particles of primary target cells expressing the activated form of LFA-1. To evaluate in a more physiological setting the effect mediated by the LFA-1 activation state on infection by ICAM-1-bearing virions, we performed similar experiments by using PHA-P-stimulated PBMCs isolated from different healthy donors as targets. A significant increase in cellular susceptibility to infection by ICAM-1/POS virions can still be seen upon treatment of the PBMCs with the LFA-1-activating NKI-L16 antibody, and this treatment had no measurable potentiating effect when infection was achieved with ICAM-1/NEG HXB-Luc virions (Fig. 3). For example, NKI-L16-mediated LFA-1 activation on the surface of PBMCs rendered these cells 44 to 56 times more susceptible to infection by ICAM-1/POS progeny viruses than to infection by ICAM-1-negative virions. Interestingly, the observed change in susceptibility of NKI-L16-treated PBMCs to viral infection was totally abrogated by pretreatment of ICAM-1-bearing HXB-Luc virions with RR1/1.1.1.
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Anti-TCR-induced activation of LFA-1 renders T cells more susceptible to infection by ICAM-1-bearing HIV-1 particles. The LFA-1 switch from low to high affinity for ICAM-1 has been reported to be transiently induced in T cells after stimulation through the TCR/CD3 complex (20). Therefore, our final goal was to induce LFA-1 high affinity for ICAM-1 by cross-linking the TCR to mimic antigen-specific T-lymphocyte cell-to-cell interactions. Results in Fig. 4 clearly demonstrate that antibody-mediated TCR stimulation of PHA-stimulated PBMCs increases their susceptibility to infection by ICAM-1/POS virions, as is the case for cells pretreated with LFA-1-activating antibody NKI-L16, while it has no detectable effect on cells inoculated with ICAM-1-free viruses. Interestingly, the kinetics of transient susceptibility to infection with ICAM-1-bearing progeny viruses, with a peak at 10 min, parallels the kinetics of the TCR-stimulated increase in LFA-1 affinity previously determined by Dustin and Springer when analyzing a cell-to-cell conjugate (20). These findings thus support the notion that the enhancement of cell susceptibility to infection with virions bearing host-derived ICAM-1 glycoproteins is due to the physical interaction between virion-bound host ICAM-1 glycoproteins and surface LFA-1 in the high-affinity state.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The important role played by LFA-1 in cell-to-cell transmission of HIV-1 was recognized several years ago (32). However, its role in cell-free virus infection has been less well studied. In this study, our primary goal was to determine how the well-known conformational change in LFA-1 could affect the process of infection by ICAM-1-bearing HIV-1 particles.
In the context of the T-cell/antigen-presenting cell encounter, the increase in ICAM-1 binding strength following stimulation allows a stronger and longer interaction between the cells, thus permitting adequate signal exchange and optimal activation. Lymphoid organs are the anatomic sites where the generation of an immune response takes place. Propagation of antigen-specific immune responses occurs in these anatomic structures, since the lymphocytes migrate from the circulation and the lymphatics into secondary lymphoid organs, particularly the lymph nodes, during the antigen-specific immune response (47). In HIV-1-infected individuals, a heavy viral load is present in the lymphoid organs, at every stage of the disease, making them the major viral reservoirs (44). Moreover, in HIV-1-infected individuals, 25 to 50% of the CD4+ T cells found in lymph nodes are in an activated state and this strong activation is kept all through the evolution of the disease due to the constant stimulation of CD4+ T cells by the continuous presence of the immunogenic virions (45, 46).
With the experiments described in this paper, we have demonstrated that activation of LFA-1 on the surface of target T cells renders them much more susceptible to infection by ICAM-1-bearing HIV-1 particles than to infection by ICAM-1-negative virions. With the knowledge that clinical HIV-1 isolates grown on PBMCs do incorporate ICAM-1 on their surfaces (11) and taking into account the fact that T-cell activation leads to increased ICAM-1 binding, it is tempting to speculate that ICAM-1-bearing viruses should give rise to a more productive infection in the constantly activated environment prevailing in secondary lymphoid organs. This hypothesis is supported by the demonstration that 5 to 10 times more HIV-1-infected cells are detected in the lymphoid organs (lymph nodes, adenoids, and tonsils) than in peripheral blood (44).
It is also known that HIV-1 particles found trapped in the web of the dendritic cells are still infectious, even though they are covered with neutralizing antibodies and complement (30). Indeed, it has been demonstrated that the follicular dendritic cells covered by trapped virions can potently transmit cytopathic infection to CD4+ T cells, although the mechanism by which these neutralizing antibody-coated virions are still infectious is undefined (30). Berman and Nakamura demonstrated that in a cell-to-cell fusion system the presence of ICAM-1 on gp120-expressing cells is associated with a decrease in the ability of neutralizing antibodies to block syncytium formation (7). It has also been observed that ICAM-1-bearing virions are less susceptible to antibody-mediated neutralization than are their viral counterparts lacking host-encoded ICAM-1 on their surfaces (49). In view of the results shown in the present paper and in previously published work, it can be proposed that virion-bound host ICAM-1 could be partly responsible for the vigorous transmission of virus infection by dendritic cells despite a strong immune response. Activation of T cells by the dendritic cellular network coated with virions during antigen presentation could render these cells more susceptible to viral infection by at least two non-mutually exclusive processes: first, by creating in T cells an intracellular milieu favorable to HIV-1 reverse transcription and integration (57, 60) and, second, as shown in our study, by strengthening the LFA-1/ICAM-1 interaction.
Our experimental design (i.e., a definite and standard incubation period to allow virus binding and entry) and the observation that pretreatment of ICAM-1-bearing virions with anti-ICAM-1 antibodies completely abrogates the higher susceptibility of cells expressing activated LFA-1 to infection with such HIV-1 particles (Fig. 3) have led us to propose the following mechanism to explain our findings. We postulate that the presence of activated LFA-1 strengthens the adhesion of ICAM-1-positive virions to target cells, ultimately resulting in greater susceptibility to virus infection due to a more efficient virus entry process (Fig. 5). However, due to the signaling nature of the LFA-1 molecule, we cannot rule out completely the possibility that some antibody-mediated outside-in signaling could alter the virus entry process by, for example, bringing CXCR4 into close proximity to LFA-1, thus favoring more efficiently entry of LFA-1-bound virions into the cell. It has been suggested that although a single gp120-CD4 interaction might be sufficient to lead to viral binding, numerous gp120-CD4 interactions are necessary to achieve virus adsorption and penetration (38). Therefore, after taking into account the reported weak association between gp120 and gp41 (25, 26), a phenomenon seen in vivo (26) that is linked with the loss of HIV-1 infectivity (42), the additional interactions between virions and target cells could compensate for a suboptimal number of gp120-CD4 associations. The initial binding event must then be rapid and strong to lead to efficient docking of the virus to its host cell. The interactions between virion-bound ICAM-1 and cell surface-activated LFA-1 will therefore result in increased efficiency or specificity of viral binding. It is possible that virus binding is analogous to adhesion of lymphocytes to endothelium, which involves initial binding to a first receptor to capture the lymphocyte, followed by binding to a second receptor (37). Secondary ICAM-1/LFA-1 interactions may allow the virus to browse the surface of the target cell until it finds the appropriate chemokine coreceptor.
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Previous studies have indicated that virus preparations from lymphoid cells are contaminated with microvesicles loaded with host proteins (8, 27). Data from our experiments permit us to rule out the possibility that higher susceptibility of T cells to infection by ICAM-1-bearing virions is not an indirect effect resulting from interactions between cellular contaminants and target cells. This postulate is based on the observation that incubation of studied T-cell lines with anti-LFA-1 antibodies (MEM83 and NKI-L16), a treatment which would induce cross-linking of surface LFA-1 molecules, as would be the case with ICAM-1-bearing microvesicles, neither activates HIV-1 LTR activity nor leads to increased susceptibility to infection by ICAM-1/NEG virions (Fig. 1 and 2). Moreover, the putative involvement of cellular contaminants in the observed phenomenon is unlikely considering that no host-derived ICAM-1 proteins could be detected in ultracentrifuged cell-free supernatants from 293T cells transiently expressing surface ICAM-1 (data not shown).
In summary, we have demonstrated that LFA-1 activation leads to a marked increase in the susceptibility of target T cells to infection by ICAM-1-bearing HIV-1 particles. Since clinical HIV-1 isolates do acquire host-encoded ICAM-1 glycoproteins, our observations have direct physiological relevance, as the incorporation process could help the virus to more efficiently target activated CD4+ T cells, which are known to contain an intracellular milieu favorable to productive viral infection and replication. LFA-1 has been previously shown to be important in HIV-1-mediated syncytium formation (32, 43). Therefore, it would be of interest to investigate whether the conformational state of LFA-1 can influence HIV-1-dependent cell-to-cell fusion events. Our study reinforces the idea that virally acquired host cell membrane molecules may play an important role in the pathogenesis of HIV-1 infection. Further studies are thus needed to better understand the role played by host molecules in the viral life cycle and how they could interfere with or be used in the design of new therapeutic strategies aimed at controlling this retroviral infection.
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ACKNOWLEDGMENTS |
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We thank B. Barbeau for critical reading of the manuscript.
This study was supported by a grant to M.J.T. from the Medical Research Council of Canada (MT-14438). M.J.T. is the recipient of a scholarship from the Fonds de la Recherche en Santé du Québec (FRSQ). J.-F.F. is supported by a National Health Research and Development Program (NHRDP) Ph.D. fellowship. R.C. is the recipient of a Ph.D. fellowship from the FRSQ/Fonds pour la Formation de Chercheurs et l'Aide à la Recherche.
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FOOTNOTES |
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* Corresponding author. Mailing address: Centre de Recherche en Infectiologie, RC709, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 boul. Laurier, Ste-Foy, Québec, Canada G1V 4G2. Phone: (418) 654-2705. Fax: (418) 654-2715. E-mail: Michel.J.Tremblay{at}crchul.ulaval.ca.
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Abstract
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Results
Discussion
References
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