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Journal of Virology, June 1999, p. 5207-5213, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Human Immunodeficiency Virus Type 2 Produces a
Defect in CD3-
Gene Transcripts Similar to That Observed for
Human Immunodeficiency Virus Type 1
Iris
Segura,1,
Christine
Delmelle-Wibaut,1,
Michel
Janssens,2
Yvette
Cleuter,3
Anne
van den
Broeke,3
Richard
Kettmann,4 and
Karen
E.
Willard-Gallo1,3,*
International Institute of Cellular and
Molecular Pathology, B1200 Brussels,1
SmithKline Beecham Biologicals, B1330
Rixensart,2 Department of Molecular
Biology, University of Brussels, B1640
Rhode-St.-Genèse,3 and
Department of Molecular Biology, Faculty of Agronomy,
Gembloux,4 Belgium
Received 28 December 1998/Accepted 1 March 1999
 |
ABSTRACT |
T cells are central players in the immune response to infectious
disease, with the specificity of their responses controlled by the
T-cell receptor (TCR)/CD3 complex on the cell surface. Impairment of
TCR/CD3-directed CD4+ T-cell immune responses is frequently
observed in individuals infected with human immunodeficiency virus
types 1 and 2 (HIV-1 and HIV-2). Virus replication is also regulated by
T-cell activation factors, with HIV-1 and HIV-2 responding to different
TCR/CD3-directed cellular pathways. We previously demonstrated that
HIV-1 infection of the human interleukin-2-dependent CD4+
T-cell line WE17/10 abrogates TCR/CD3 function and surface expression by a specific loss of CD3-
gene transcripts. In this study, we show
that HIV-2 provokes the same molecular defect in CD3- gene transcripts, resulting in a similar but delayed progressive loss of
TCR/CD3 surface expression after infection.
| |
TEXT |
The principal etiologic agent of
AIDS is human immunodeficiency virus type 1 (HIV-1) (5, 24),
although infection with HIV-2 (16, 38), a related lentivirus
found predominantly in West Africa, produces a clinically similar
disease. An important pathogenic difference between these viruses is
that disease develops much more slowly in HIV-2-seropositive than in
HIV-1-seropositive individuals (52). While this difference
remains largely unexplained, it is thought that there is a correlation
between clinical evolution and viral activities at the cellular level.
Many studies have compared HIV-1 and HIV-2 gene expression and function
as well as their genetic diversity in an effort to identify the
molecular basis for this variation in viral pathogenesis. HIV-1 and
HIV-2 have significant sequence divergence (±40% homology, depending
on the variant) (29), although the two viruses are similar
in genomic organization, share mechanisms of transactivation, and
encode gene products with biologically similar functions (23, 90). Replication of both HIV-1 and HIV-2 is transcriptionally regulated in response to T-cell activation factors; however, each virus
has a specific set of transcriptional control elements contained within
its LTR (long terminal repeat), with enhancer stimulation mediated by
different sets of activation-induced cellular proteins (32, 33,
44, 50, 51, 70). For example, monoclonal antibodies to the T-cell
receptor (TCR)/CD3 complex stimulate production of HIV-2 but not HIV-1
from latently infected T-cell lines, while HIV-2 is less responsive
than HIV-1 to stimulation by tumor necrosis factor alpha
(32).
Impairment of the TCR/CD3 activation pathway is often observed early in
disease progression after HIV-1 infection, with functional loss of
receptor-directed immune responses found in T cells from asymptomatic
HIV-1-seropositive individuals and patients with AIDS (17, 34, 43,
55, 62, 66). The molecular or cellular processes defining the
relationship between viral gene transcription and TCR/CD3-regulated
pathways have not yet been identified. However, in vitro studies have
described suppression of TCR/CD3-directed activation by the virally
encoded proteins gp120 (13, 22, 45, 56, 60, 68), Nef
(25, 35, 46, 63), and Tat (54, 66, 77). Recently,
CD3 expression was found to be quantitatively reduced with advancing
disease stages on both activated and resting CD4+ and
CD8+ T cells from HIV-1-infected individuals
(27). Other studies found that the TCR/CD3 signaling chain
CD3-
, but not CD3-
, was significantly decreased in T cells from
symptomatic AIDS patients as well as those from individuals in the
acute and early asymptomatic stages of HIV-1 infection (64,
71). These studies used flow cytometry to quantify the amount of
CD3- and CD3- protein present but did not examine mRNA
transcripts for any of the receptor chains. CD3- has a significant
role in TCR/CD3 receptor signal transduction (36, 58, 59),
but recent studies show that it is rapidly turned over independent of
TCR/CD3 complex formation and surface expression, suggesting that it
may not be a critical assembly and transport limiting factor for
surface expression (57). Alternatively, many studies have
shown that CD3- plays a critical role in receptor downregulation
after engagement and triggering of the TCR/CD3 complex (8, 10-12,
19-21, 31, 41, 48, 79). We previously demonstrated that
productive HIV-1 infection of the interleukin-2 (IL-2)-dependent CD4+
T-cell line WE17/10 abrogates TCR/CD3 surface expression due to a
specific defect in CD3- gene transcripts (84).
Examination of receptor density on the surface of WE17/10 cells
revealed that TCR/CD3 complexes (and CD3- gene transcripts) are
quantitatively reduced early after HIV-1 infection, and receptor function and expression are progressively impaired (83).
Thus, the defect in CD3- gene transcripts observed in HIV-1-infected WE17/10 cells causes a progressive loss of receptor surface expression and function as the cells transition from TCR/CD3hi to
TCR/CD3lo to TCR/CD3
.
We questioned whether the diversity of HIV-1 genotypes and phenotypes
or cellular selection pressures generated in vitro was responsible for
this progressive decrease in TCR/CD3 surface complexes. We found that
interference with CD3- gene transcripts was not restricted to
infection with a given HIV-1 variant or to changes in HIV-1
quasispecies during in vitro infection (83). Furthermore, the absence of changes in the viability or doubling times of the chronically infected cells, the spontaneous reversion of CD3- downmodulation in two HIV-1 infected cell lines, and the consistent appearance of the intermediate TCR/CD3lo phenotype strongly
suggest that in vitro selection of a CD3- chain mutant subpopulation
does not account this defect (83). In our ongoing
search for a link between viral and cellular regulatory processes that
play a role in these events, we asked whether loss of CD3- gene
expression was specific for infection with HIV-1 and therefore related
to differences in the responsiveness of the HIV-1 and HIV-2 LTRs to
T-cell activation factors. Evidence presented in this study shows that
HIV-2 infection of WE17/10 cells also provokes a loss of CD3- gene
transcripts, characterized by progressive diminution of TCR/CD3 surface
density, which parallels but is delayed in comparison with that
previously reported for HIV-1 (83, 84).
Infection of WE17/10 cells with HIV-1 and HIV-2.
The WE17/10
cell line is a human IL-2-dependent CD4+ T-cell line that
was established and characterized as previously described (84). WE17/10 cells were synchronized by IL-2 deprivation
and infected with 0.1 infectious unit of HIV-1 or HIV-2 per cell as previously described for HIV-1 (83, 84). Control WE17/10
cells were mock infected and carried in parallel passages for each
infection experiment. The HIV-2 variants HIV-2MS
(from Phyllis Kanki) and HIV-2MVP-15132
(28) (referred to here as HIV-2MVP; from Lutz Gürler and Friedrich Deinhardt) were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of
Health. The LAV-1 strain (5) (now known to be HIV-1 strain Lai [78]) was provided by F. Barré-Sinoussi; the
molecularly cloned HIV-1 genome, HXB2 (61), was obtained
from B. Hahn and G. M. Shaw through the AIDS Research and
Reference Reagent Program.
For the first 3 weeks following infection, fractions of the infected
and uninfected cell cultures were removed every 2 to 3 days, counted
for viability by trypan blue exclusion, and fixed and stained by
indirect immunofluorescence. The cells were labeled with
immunoglobulins purified from a pool of HIV-1- or HIV-2-positive human sera followed by fluorescein-conjugated goat anti-human immunoglobulin G (DAKO A/S, Glostrup, Denmark) and counted to determine the percentage of infected cells. HIV-1/HIV-2 viral antigen
(p24/p26) content in the culture supernatant was determined by the
Innotest HIV-1/HIV-2 antigen enzyme-linked immunosorbent assay
(Innogenetics, Gent, Belgium).
WE17/10 cells acutely infected with either HIV-1
(WE/HIV-1HXB2 or WE/HIV-1LAI) or HIV-2
(WE/HIV-2MS or WE/HIV-2MVP) exhibited decreased cell viability and a progressive decline in growth rate during the peak of virus production that followed 100% infection. The
maximum levels of viral p24/26 antigen at the peak of acute infection
were consistently between 180 and 200 ng/ml for cells infected with the
HIV-1 isolates and between 160 and 180 ng/ml for cells infected with
the HIV-2 isolates. The maximum levels were slightly lower for the
HIV-2 isolates than for the HIV-1 isolates, possibly a reflection of
subtle differences in the sensitivity of the Innogenetics
HIV1/HIV-2 antigen enzyme-linked immunosorbent assay for each virus. In
10 experimental infections with either HIV-1LAI or
HIV-1HXB2, 100% of WE17/10 cells were productively infected after an average of 17 days postinfection (p.i.; range, 11 to
24 days). In eight experimental infections with either
HIV-2MS or HIV-2MVP, 100% of WE17/10 cells
were productively infected after an average of 15 days p.i. (range, 7 to 25 days). This acute, productive phase of infection generally lasted
for 1 to 2 weeks and was followed by a quiescent period during which
the cells grew slowly. Normal growth (doubling time, ±24 h) returned
within the following 3 weeks, and these chronically infected cell lines could be maintained in culture indefinitely thereafter. The patterns of
acute infection were quite similar for all of the
WE/HIV-1HXB2, WE/HIV-1LAI,
WE/HIV-2MS, and WE/HIV-2MVP cell lines. It is
important to note that some of the original virus isolates required
mycoplasma decontamination before this typical progression of acute
infection was observed (data not shown).
TCR/CD3 and CD4 surface expression after HIV-1 or HIV-2 infection
of WE17/10 cells.
Kinetic changes in the amount of CD2, CD3,
CD4, and CD5 expressed on the surface of the infected
WE/HIV-1HXB2, WE/HIV-1LAI, WE/HIV-2MS, and WE/HIV-2MVP cell lines, in
comparison with the mock-infected WE17/10 cell line, were monitored
for 50 to 60 weeks p.i. The murine monoclonal antibodies used included
OKT.3 (anti-CD3; Ortho Diagnostic Systems, Beerse, Belgium),
OKT.4 (anti-CD4 that recognizes a non-HIV-1 binding epitope;
Ortho), Leu-1 (anti-CD5; Becton Dickinson, Erembodegem-Aalst, Belgium;
negative control [data not shown]), and Leu5b (anti-CD2; Becton
Dickinson). The cells were labeled and analyzed on a FACStar Plus
(Becton Dickinson) as previously described (83, 84). The
WE17/10, WE/HIV-1, and WE/HIV-2 cell lines all consistently and
uniformly expressed CD2 (positive control) on 100% of the cell
population after infection. The mean fluorescence values for CD2 on the
infected cells were routinely equal to or higher than values for the
mock-infected cells, as previously described by others (27).
A significant reduction in CD4 surface expression was detected in all
of the productively infected WE/HIV-1
HXB2,
WE/HIV-1
LAI (Table
1), WE/HIV-2
MS, and
WE/HIV-2
MVP (Table
2) cell
lines.
This decrease was due to a decline
in CD4 mean fluorescence, which
was characterized by a loss of receptor
surface density on 100%
of the cells rather than the appearance of
a CD4-negative subpopulation
(
84). In general, CD4 surface expression on the
WE/HIV-1
HXB2 and WE/HIV-2
MS cell lines declined
to 10 to 20% of the values
for the mock-infected WE17/10 cells after
the acute phase of infection.
Alternatively, loss of CD4 surface
receptor density on the WE/HIV-1
LAI and
WE/HIV-2
MVP cell lines was less substantial, with a maximum
drop to 30 to 45% of control values. These chronically infected
WE/HIV-1 and WE/HIV-2 cell lines all maintained their low CD4
expression levels during the year-long infection experiment. The
level
of p24/26 antigen detected in the culture supernatant of
the
chronically infected WE/HIV-1 and WE/HIV-2 cell lines declined
over
time p.i. in a manner similar to that previously described
for HIV-1
(
83). However, this decrease was not correlated with
alterations in the level of CD4 surface density (data not shown).
The
lower CD4 surface expression found on cells infected with
HIV-1
HXB2 and HIV-2
MS compared to cells
infected with HIV-1
LAI and HIV-2
MVP may reflect
differences in the expression of one
or more specific viral gene
products. The viral proteins Vpu (
85,
86), Env
(
13), and Nef (
1,
2) have all been shown to
be
independently capable of downmodulating CD4, with Nef active
in the
early phase of virus infection and Vpu (expressed only
in HIV-1)
(
65) and Env acting in the later stages of infection
(
14). The combination of all three is more effective than
any
one or two, with their concerted actions required for maximal
downmodulation of CD4. This finding suggests that expression of
Env
and/or Nef may be lower in the WE/HIV-1
LAI and
WE/HIV-2
MVP cell lines than in the WE/HIV-1
HXB2
and WE/HIV-2
MS cell lines.
Loss of TCR/CD3 receptor complexes on the surface of both HIV-1- and
HIV-2-infected cells follows a pattern that is distinct
from that
observed for CD4. Immediately following the early acute/cytopathic
phase of infection (generally between 3 and 5 weeks p.i.), 99
to 100%
of the cells were TCR/CD3
+ (comparable to the mock-infected
cells). Subsequent, systematic
kinetic analysis of the chronically
infected cell lines revealed
the initial appearance of 5 to 10%
TCR/CD3
cells at between 6 and 16 weeks in 10 WE/HIV-1
LAI and WE/HIV-1
HXB2 cell lines (the
kinetics of receptor loss for several WE/HIV-1
cell lines are shown
either in Fig.
1A or in previous
publications
[
83,
84]) and after 16 to 34 weeks in
eight WE/HIV-2
MS and
WE/HIV-2
MVP cell lines
(representative experiments are shown in
Fig.
1B).
TCR/CD3
cells were defined for each experimental time
point as those
outside the region delineated by the mock-infected
control. The
kinetics shown in Fig.
1 illustrates that
TCR/CD3
cells appear earlier in HIV-1-infected than in
HIV-2-infected
cells. The relevance of this observation to known
differences
in the rate of disease development after in vivo infection
with
HIV-1 or HIV-2 (
52) is unknown. Once the cell
population drops
below 80% TCR/CD3
+ cells, a steady
decline to the TCR/CD3
phenotype generally ensues;
however, the rate of progression
to a majority of receptor-negative
cells can vary widely between
isolates of both HIV-1 and HIV-2.
Occasionally, this progressive
downregulation of receptor expression
was temporarily observed
to spontaneously reverse itself in some of the
infected cell lines
(such as that seen for WE/HIV-2
MS and
to a lesser extent WE/HIV-1
LAI in Fig.
1). Overall, we
found that while there was kinetic variation,
the sequences of changes
in TCR/CD3 surface expression were similar
for the HIV-1- and
HIV-2-infected cell lines.
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FIG. 1.
Evolution of TCR/CD3 surface expression for
WE/HIV-1LAI and WE/HIV-1HXB2 cells (A) and
WE/HIV-2MVP and WE/HIV-2MS cells (B) in
comparison with the mock-infected WE17/10 controls. The
TCR/CD3+ cell population is defined as the percentage of
anti-CD3 labeled cells that fall within the region defined by the
histogram of the uniformly positive mock-infected WE17/10 cells.
|
|
Modulation of TCR/CD3 surface density after infection of WE17/10
cells with HIV-1 or HIV-2.
The mean fluorescence values, which
reflect receptor surface density, collected sequentially in the kinetic
experiments described above, provide an imprecise basis for comparison
due to minor variation in the fluorescence intensity between labeling
experiments. Therefore, we serially cryopreserved each cell line during
the initial year-long infection experiment and determined that when thawed, these cells retained the phenotype that they had on the day
that they were frozen. This cell bank enabled us to perform a
retrospective, quantitative analysis on a series of sequential samples
from each of the infected cell lines. TCR/CD3 surface receptor density
was found to progressively decrease p.i. on all of the
WE/HIV-2MS (Fig. 2) and
WE/HIV-2MVP cell lines in a manner similar to that
previously described for HIV-1 (83). Initially, following
the acute/cytopathic stage of infection, all of the cells are
TCR/CD3hi. Shortly thereafter, receptor downregulation from
TCR/CD3hi to TCR/CD3lo occurs and is
characterized by a decrease in receptor density from 100% to 50% of
control values of cells lying outside the region defined by the
negative control. The initiation of this decline in receptor surface
density was also retarded in the HIV-2-infected cells (15 to 33 weeks
p.i.) compared with the HIV-1-infected cells (5 to 15 weeks p.i.),
although again variation between isolates of the same virus was
observed. Furthermore, the TCR/CD3lo phenotype could be
maintained for different lengths of time, with progression to the
TCR/CD3 phenotype slower in the WE/HIV-1LAI
and WE/HIV-2MVP cell lines than in the
WE/HIV-1HXB2 and WE/HIV-2MS cell lines. These
kinetic differences in the progressive disruption of TCR/CD3 surface
expression found between isolates possibly reflects their relative
efficiency at performing specific viral processes, their ability to
subvert cellular control mechanisms, or changes in the composition of viral gene products expressed during the course of in vitro infection.
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FIG. 2.
Histograms showing the distribution of
immunofluorescence from anti-CD3 antibody staining as a function of
time p.i. From top to bottom: uninfected WE17/10 cells, and the
WE/HIV-2MS cell line at 15, 21, 35, 51, and 60 weeks p.i.
TCR/CD3lo cells are identified as cells that fall below the
minimum fluorescence intensity defined by the positive control but do
not lie within the region defined by the negative control.
TCR/CD3hi cells fall within the region defined by
mock-infected WE17/10 cells, and TCR/CD3 cells fall
within the region designated by the negative control.
|
|
TCR/CD3 mRNA expression in HIV-1- and HIV-2-infected cell
lines.
RNA was isolated from approximately 5 × 108 cells by the single-step method of Chomczynski and
Sacchi (15), followed by oligo(dT)-cellulose selection of
poly(A)+ RNA and dotting of 1.0 µg per sample on
nitrocellulose membranes. RNA extracted from an ovine kidney cell line
(OVK) was used as a negative control. The membranes were hybridized for
16 h under stringent hybridization conditions using the following
[
-32P]dCTP-labeled probes (each at 3 × 106 cpm/ml): CD3- (pJ; kindly provided by M. J. Crumpton [42]); CD3-
(p; obtained from the
American Type Culture Collection [75]); CD3-
(kindly provided by A. Weissman [82]); CD3- (pSR-, kindly provided by B. Alcaron [6]);
TCR- and TCR-
(kindly provided by T. Mak [87,
88]); HIV-1 (pBH10 [30]) and HIV-2
(pJSP4-27/H6 [40]), obtained from B. Hahn and G. M. Shaw through the AIDS Research and Reference Reagent Program; and
-actin (Clontech, Heidelberg, Germany).
The molecular defect underlying the TCR/CD3
phenotype of
HIV-1-infected WE17/10 cells was previously shown, by RNA dot and
Northern blot hybridization (
84), to result from a specific
defect in CD3-
gene transcripts. In this study, RNA dot blot
hybridization was used to verify whether downmodulation of receptor
expression on HIV-2-infected WE17/10 cells is also due to the
specific
loss of CD3-
gene transcripts. The blots shown in Fig.
3 confirm that the amounts of TCR-
,
TCR-
, CD3-
, CD3-
, and
CD3-
mRNAs do not change after
infection in WE/HIV-1 or WE/HIV-2
cell lines expressing different
levels of surface TCR/CD3 complexes.
The signals for CD3-
and
CD3-
mRNA are weaker than those for
the other four chains,
reflecting their limiting roles in the
expression and signaling of
surface complexes (
80). However,
a consistent signal is
detected for CD3-
, while the CD3-
signal
progressively decreases
in correlation with the percentage of
TCR/CD3 surface complexes. Thus,
HIV-2 infection is also associated
with loss of TCR/CD3 surface
expression due to a defect in CD3-
gene transcripts. Hybridization
with a
-actin probe was used
to control for the quantity of mRNA in
each dot and revealed a
slightly lower signal for
WE/HIV-2
MS (data not shown). The HIV-1
and HIV-2 probes
were used to control that each cell line was
infected with one of the
two viruses only (data not shown). As
previously shown for
HIV-1-infected cells (
83), we demonstrate
that TCR/CD3
surface density is progressively decreased in concert
with CD3-
gene
transcripts as the HIV-2-infected cell lines transition
from
TCR/CD3
hi to TCR/CD3
lo to
TCR/CD3
.
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FIG. 3.
Expression of messages for TCR-, TCR-, CD3-,
CD3-, CD3-, and CD3- in cells from the mock-infected WE17/10
cell line and the infected WE/HIV-2MVP,
WE/HIV-2MS, WE/HIV-1HXB2, and
WE/HIV-1LAI cell lines. The filters probed with the
TCR-, TCR-, CD3-, and CD3- cDNAs were exposed for 5 days;
those probed with CD3- and CD3- cDNAs were exposed for 14 and 9 days, respectively. The percentage of TCR/CD3+ cells is
defined as described in the legend to Fig. 1.
|
|
We have provided evidence that HIV-2 infection of the WE17/10 cell line
progressively abrogates TCR/CD3 surface expression
due to a
transcription level defect in the CD3-
gene similar
to that
previously described for HIV-1 (
83,
84). Subtle changes
in
TCR/CD3 surface density could explain some of the T-cell-mediated
abnormalities observed in HIV-positive individuals, since adequate
amounts of functional surface complexes have been shown to be
critical
for mounting a successful antigen-dependent immune response
(
73,
74,
76). Impeding CD3-
gene expression inhibits TCR/CD3
surface expression both in vivo (
3,
4,
69) and in vitro
(
26,
84). In the absence of CD3-
, tetrameric
complexes
are formed and only pentameric
2
complexes have the conformation
required for stable association with
CD3-
and subsequent processing
from the endoplasmic reticulum
through the Golgi apparatus to
the plasma membrane (
7,
9,
21,
39,
49). Our current
knowledge concerning the pivotal roles that both
CD3-
and CD3-
play in TCR/CD3 assembly, expression, and function
(
81) underscores
why limiting their expression may
potentially be an important
mechanism for virus-directed control of the
immune
response.
Although kinetic differences were observed between isolates of HIV-1
and isolates of HIV-2, in general, the HIV-2 viruses
were found to be
slower than the HIV-1 viruses to manifest the
defect, both during the
transition from TCR/CD3
hi to TCR/CD3
lo and
during the transition from TCR/CD3
lo to
TCR/CD3
. These in vitro data correspond with in vivo data
showing that
the rate of disease progression is different between these
viruses,
with disease-free survival time for HIV-2 significantly longer
than that for HIV-1 (
52). Virus-specific targeting of
TCR/CD3
expression has also been observed in human T-lymphotropic virus
type 1-infected CD4
+ T cells both in vitro (
18,
89) and in vivo (
53,
67,
72),
as well as human
herpesvirus 6-infected CD4
+ T cells in vitro
(
47). The basis for the clinical differences
between these
viruses is unknown and likely depends on both virus
and host factors;
however, there is increasing evidence that an
important mechanism
whereby human retroviruses can incapacitate
their T-cell host is via
specific interference with the TCR/CD3
receptor
pathway.
T-cell activation is a critical event in an effective immune response
against a pathogen and paradoxically also contributes
to the
progressive immune dysfunction associated with HIV-1 and
HIV-2
infection by inducing factors which these viruses exploit
to enhance
their own transcription (
32,
33,
44,
50,
51,
70). A number
of studies have shown that the HIV-1 and HIV-2
LTRs are stimulated by
different T-cell activation pathways and
therefore have selective
controls for virus replication. We asked
whether there was a
correlation between infection with HIV-1 or
HIV-2 and changes in
surface expression of the TCR/CD3 complex.
We found similar defects in
CD3-
gene transcripts after infection
with both viruses, although
the rate of receptor loss varied.
Thus, our data suggest that the
progressive decrease in CD3-
gene transcripts and surface receptor
density after infection
of WE17/10 cells results from virus-host cell
interactions acting
through a mechanism(s) common to HIV-1 and HIV-2.
| |
ACKNOWLEDGMENTS |
We are indebted to P. Kanki, L. Gürler, F. Deinhardt, F. Barré-Sinoussi, B. Hahn, G. M. Shaw, B. Alcaron, M. J. Crumpton, T. Mak, A. Weissman, and the NIH AIDS Research and Reference
Reagent Program for efficiently providing various reagents. We thank
Renée Martin for excellent technical assistance.
This work was supported by grants from the Fonds National de Recherche
Scientifique (FNRS; FNRS-SIDA 3.7014.91 and FNRS-Télévie 7.4530.92), the World Health Organization (M8/181/4/5.418), and the
Poles for Interuniversity Attraction. R.K. is a Research Director of
the FNRS.
| |
FOOTNOTES |
*
Corresponding author. Present address: Department of
Molecular Biology, University of Brussels, rue des Chevaux, 67, B1640 Rhode-St.-Genèse, Belgium. Phone: (32) 2/650-9826. Fax: (32) 10/22.91.62 or 2/650-9839. E-mail:
kwillard{at}dbm.ulb.ac.be.
Present address: Centro Internacionale de Investigaciones
Médicas, Cali, Colombia.
Present address: SmithKline Beecham Biologicals, B1330 Rixensart, Belgium.
| |
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Journal of Virology, June 1999, p. 5207-5213, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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