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Journal of Virology, December 1998, p. 10251-10255, Vol. 72, No. 12
Department of Biochemistry and Molecular
Biology, Oregon Health Sciences University, Portland, Oregon 97201-3098
Received 6 July 1998/Accepted 7 September 1998
The vif gene of human immunodeficiency virus type 1 (HIV-1) encodes a basic Mr 23,000 protein that
is necessary for production of infectious virions by nonpermissive
cells (human lymphocytes and macrophages) but not by permissive cells
such as HeLa-CD4. It had been proposed that permissive cells may
contain an unidentified factor that functions like the viral Vif
protein. To test this hypothesis, we produced pseudotyped wild-type and
vif-deleted HIV gpt virions (which contain the
HIV-1 genome with the bacterial mycophenolic acid resistance gene
gpt in place of the viral env gene) in
permissive cells, and we used them to generate nonpermissive H9
leukemic T cells that express these proviruses. We then fused these H9
cells with permissive HeLa cells that express the HIV-1 envelope
glycoprotein gp120-gp41, and we asked whether the heterokaryons would
release infectious HIV gpt virions. The results clearly showed that the vif-deleted virions released by the
heterokaryons were noninfectious whereas the wild-type virions were
highly infectious. This strongly suggests that nonpermissive cells, the
natural targets of HIV-1, contain a potent endogenous inhibitor of
HIV-1 replication that is overcome by Vif.
The vif gene of human
immunodeficiency virus type 1 (HIV-1) encodes a highly basic
Mr 23,000 protein that collapses intermediate filaments (14), locates in both cytosolic and nuclear sites (11, 14), is present in small amounts in virions
(16), and is highly conserved among lentiviruses
(20). Vif protein is not essential for HIV-1 replication in
permissive cells such as HeLa-CD4 or in semipermissive cells such as
SupT1 (9, 24). However, it is necessary for production of
infectious virions by cells that are natural targets for infection,
including CD4-positive T lymphocytes and macrophages, and by the H9
line of leukemic T cells (2, 9, 28). Nonpermissive cells can
be infected by vif mutant virus made in permissive cells,
but the result is production of only weakly infectious virions that
cannot spread in cultures. Recent studies have shown that the
defectiveness of vif mutant virus made in nonpermissive
cells is not caused by gross abnormalities in protein composition
(4, 8) and cannot be overcome by assaying the virus in
permissive cells or in nonpermissive cells that contain Vif protein
(7). The defective virus enters target cells and begins
reverse transcription, but the resulting proviral DNA is prematurely
degraded (3, 7, 28). Thus, the defectiveness of
vif mutant HIV-1 conditionally depends on the cellular
source of the virus rather than on the cells used to analyze infectivity.
The above results strongly suggest that the Vif protein performs a
critical function in cells that produce HIV-1 virions. However, little
is known about this critical Vif function. It has been proposed that
permissive cells may contain a cellular protein that functions like
Vif, thereby enabling active replication of vif mutant HIV-1
(26, 27). Alternatively, nonpermissive cells might contain
an inhibitor of HIV-1 replication that is counteracted by Vif. These
distinct hypotheses have not previously been investigated.
We have addressed this issue by analyzing infectivities of wild-type
and vif mutant virions produced by heterokaryons formed by
fusion of nonpermissive H9 leukemic T cells with fully permissive HeLa
cells. Presumably, if permissive cells contain a protein that functions
like Vif, the vif mutant virions released from the
heterokaryons would be infectious. Alternatively, if nonpermissive cells contain an inhibitor that is counteracted by Vif, the
vif mutant virions made by the heterokaryons would be inactive.
A schematic outline of this genetic complementation experiment is shown
in Fig. 1. The strategy involves
production of wild-type and vif-deleted HIV gpt
virions. pHIV-gpt encodes the HIV-1 provirus HXBII, with the
bacterial gpt gene for mycophenolic acid resistance substituted for the viral env gene (21). This
plasmid was modified to construct
pHIV-vif-deleted-gpt by digestion with
SalI and NdeI restriction endonucleases (New
England Biolabs, Beverly, Mass.), blunting with the Klenow fragment of
DNA polymerase I (Life Technologies, Grand Island, N.Y.), and
incubation with T4 DNA ligase (Life Technologies) to allow self
ligation. This deleted a large portion of the vif gene and
also removed a portion of the vpr gene. However, since the
nonessential accessory genes vpr, vpu, and
nef are all defective in the HXBII molecular clone of HIV-1
(with vpr having a mutation in the initiation codon)
(19), this deletion did not have any effect on virus
production (see below). Step 1 involved cotransfection of fully
permissive COS-7 cells with pSVIII-env, encoding HXBII envelope, plus either pHIV-gpt or
pHIV-vif-deleted-gpt by the DEAE-dextran with
chloroquine transfection protocol (1). COS-7 cells were
propagated as described previously (22). As shown by Western
blotting, the transfected COS-7 cells expressed HIV-1 Gag proteins to
equal extents, indicating that deletion of vif did not
inhibit expression of the HIV gpt provirus (see Fig. 2). Moreover, these transfected COS-7 cells released equal titers of the
wild-type and vif-deleted HIV gpt viruses. For
example, in a representative experiment when 4 ml of cell-free media
from wild-type and vif-deleted HIV
gpt-transfected COS-7 cells was used to infect HeLa-CD4
cells, we obtained titers of 3,250 and 3,050 colonies per
100-mm-diameter culture dish for wild-type and vif-deleted
HIV gpt, respectively. Therefore, COS-7 cells are fully
permissive. In step 2, the virus-producing monolayers of adherent COS-7
cells were cocultured with a suspension of nonpermissive H9 T cells;
48 h later, the newly infected H9 cells were removed into fresh
cultures. The resulting suspensions of H9 cells appeared morphologically homogeneous and did not produce any infectious HIV
gpt virions, indicating that they were not significantly
contaminated with the virus-producing COS-7 cells. Other control
studies substantiated this conclusion (results not shown). As
illustrated by Western blotting (Fig.
2A), the H9 cells that had been infected
with these wild-type and vif-deleted HIV gpt
virions reproducibly expressed similar amounts of the HIV-1 p55 and
p24gag core proteins. This suggested that the
infections in step 2 occurred with similar efficiencies and that
processing of the core p55gag polyproteins in
nonpermissive H9 cells was not significantly altered by the
vif deletion. As also shown by Western blotting (Fig. 2B),
the Mr 23,000 Vif protein was present in H9
cells that had been infected with wild-type HIV gpt virus
but was absent from cells that had been infected with the
vif-deleted HIV gpt virus. In step 3, the
infected H9 cells were mixed with a clone of tetracycline-inducible
HeLa-gp160 cells that expressed the HIV-1 IIIB env gene.
These cells were generated by transfecting HeLa-tTA (12)
cells with pUHD10-3(gp160/rev) by the calcium phosphate
transfection method (1). pUHD10-3(gp160/rev) was constructed by cloning an XbaI 2.9-kbp gp160/rev
fragment from pGCneo/gp160-rev (21a)
into the same site of the tetracycline-responsive plasmid pUHD10-3.
Figure 3 presents evidence that our clone
of HeLa-tc-gp160 cells expressed abundant gp120-gp41 Env glycoproteins when they were induced by removal of tetracycline from the medium. We
also used the methods described above for COS-7 cells and confirmed that this clone of HeLa-tc-gp160 cells was fully permissive for HIV-1
production. Moreover, the induced cells formed abundant syncytia when
they were cocultured in step 3 with the infected H9 cells (Fig.
4). Staining of the rinsed monolayers
after this coculturing of HeLa-tc-gp160 cells with the suspension of
CD4-positive H9 HIV gpt or H9 vif-deleted HIV
gpt cells showed equal numbers of syncytia. Thus, in one
experiment these two monolayers contained 29% ± 3% and 27% ± 4%
of the total nuclei in syncytia, respectively. Because uninfected H9
cells could also form syncytia with induced HeLa-tc-gp160 cells, we
isolated stable populations of H9 HIV gpt and H9
vif-deleted HIV gpt cells by selection with
mycophenolic acid. In control experiments, we found that these selected
cells and the control uninfected H9 cells all formed syncytia with
HeLa-tc-gp160 cells to equal extents. Moreover, the H9 cells that
stably expressed the HIV gpt proviruses contained the same
quantities of cell surface CD4 as the uninfected H9 cells, as
determined by binding a monoclonal antibody to CD4 followed by
125I-protein A (13). Consequently, there was no
effect of vif expression on cellular quantities of CD4 or on
the ability of H9 cells to fuse with the induced HeLa-tc-gp160 cells.
Because vpu and nef genes can down-modulate CD4
expression (5), their absence from the HXBII-derived
pHIV-gpt provirus (19) was presumably a positive factor in enhancing syncytium formation in step 3. It is noteworthy that many of the syncytia contained giant nuclei or nuclei of widely
divergent sizes. It is believed that these are generated after
heterokaryons proceed through aberrant mitoses and the nuclear membranes then reform around groups of intermixed chromosomes (18). This morphological feature suggests that the nuclear
contents within the syncytia had substantially intermixed by 24 to
48 h after initiation of step 3.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
An Endogenous Inhibitor of Human Immunodeficiency
Virus in Human Lymphocytes Is Overcome by the Viral Vif
Protein
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FIG. 1.
Schematic diagram of the vif complementation
assay. In step 1, COS-7 cells at 80% confluency in a 100-mm culture
dish were cotransfected with 5 µg of wild-type (Wt)
pHIV-gpt or pHIVvif-deleted-gpt and 5 µg of pSVIIIenv. In step 2, suspensions of nonpermissive
H9 leukemic T cells were added to the virus-producing COS-7 monolayers
for 48 h. In step 3, the H9 cells were separated from the
monolayer and cocultured with induced HeLa-tc-gp160 cells. This
resulted in spontaneous cell fusion to produce heterokaryons, and virus
was harvested from the culture media after 24, 48, and 72 h. In
step 4, virus was filtered (0.45-µm-pore-size filters) and then used
to infect HeLa-CD4 (H1-J clone) cells. In step 5, infected HeLa-CD4
cells were seeded in a 100-mm culture dish and selected with medium
containing mycophenolic acid (MPA) (40 µg/ml). Mycophenolic
acid-resistant colonies were fixed, stained, and counted after 15 to 21 days of selection (22).
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FIG. 2.
Western immunoblot analyses of viral protein production
in transfected COS-7 and infected H9 cells. H9 cells were cocultured
with transfected virus-producing COS-7 cells as described in the legend
to Fig. 1. At 72 h posttransfection of COS-7 cells (5 × 106 cells per 100-mm culture dish) and 48 h
postinfection of H9 cells (1 × 106 cells), extracts
of control and transfected or infected cells were obtained by washing
the cells in phosphate-buffered saline (Life Technologies), followed by
cell lysis in sodium dodecyl sulfate-polyacrylamide gel electrophoresis
sample buffer (62.5 mM Tris-HCl [pH 6.8], 10% glycerol, 2% sodium
dodecyl sulfate, 0.1% bromophenol blue, 10% 2-mercaptoethanol). The
samples were then boiled, and equal amounts were loaded onto 10%
polyacrylamide gels in the presence of 0.1% sodium dodecyl sulfate and
subjected to electrophoresis. The proteins were then electrotransferred
to nitrocellulose membranes and used for immunoblotting
(21). Viral proteins were detected by incubating the
membranes with HIV-IG antiserum (A) (obtained through the National
Institutes of Health [NIH] AIDS Research and Reference Reagent
Program, donated by Alfred Prince) or with HIV-1HXB2 Vif
antiserum (B) (obtained through the NIH AIDS Research and Reference
Reagent Program, donated by Dana Gabuzda) at a 1:1,000 dilution in 5%
milk-0.1% Tween 20-Tris-buffered saline (Bio-Rad Laboratories,
Hercules, Calif.), followed by protein A-conjugated horseradish
peroxidase (HRP) at a 1:10,000 dilution (Bio-Rad). Antibody binding was
then detected with a phototope-HRP Western blot detection kit (New
England Biolabs). Mrs are indicated on the left,
in thousands. Wt, wild type.
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FIG. 3.
Western immunoblot analysis showing induced expression
of gp160 upon removal of tetracycline (TC) from HeLa-tc-gp160 cells.
HeLa-tc-gp160 cells were seeded in a 25-cm2 tissue culture
flask and grown in the absence or presence of tetracycline (0.5 µg/ml; Sigma). Total cell extracts were collected 48 h later.
Protein concentrations were measured by the Bio-Rad Bradford assay, and
20 µg of protein was analyzed by electrophoresis and immunoblotting,
as described in the legend to Fig. 2. The blot was developed with a
1:1,000 dilution of sheep anti-gp120 antiserum (obtained through the
NIH AIDS Research and Reference Reagent Program, donated by Michael
Phelan), followed by protein G-conjugated horseradish peroxidase at a
1:5,000 dilution (Bio-Rad) and detection as described in the legend to
Fig. 2.
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FIG. 4.
Formation of syncytia by coculturing of HeLa-tc-gp160
and infected H9-42 (vif-deleted HIV gpt) cells.
(A) HeLa-tc-gp160 cells grown in the presence of tetracycline do not
synthesize gp160 or fuse with H9-42 cells. HeLa-tc-gp160 cells (3 × 105) were seeded in a 25-cm2 tissue culture
flask and grown for 2 days in medium containing 0.5 µg of
tetracycline (Sigma) per ml before H9 cells (4 × 106)
were added. The cocultures were then grown for 48 h. Cells were
observed under light microscopy after removal of the medium and
unabsorbed cells, rinsing of adherent cells with phosphate-buffered
saline (Life Technologies), fixing of cells with cold 100% methanol,
and staining of cells with 0.1% toluidene blue in 30% ethanol. (B) H9
cells infected with vif-deleted HIV gpt were
added to HeLa-tc-gp160 cells that were grown in the absence of
tetracycline. Heterokaryons were allowed to form for 48 h. The
cells were then fixed and stained as described for panel A. The small
round darkly stained cells in both panels are H9 cells that adhered to
the monolayers and were not removed by rinsing. Indistinguishable
results were obtained with H9 cells that expressed wild-type HIV
gpt (see text). Magnification, ×800.
In steps 4 through 6, virus produced by the heterokaryons was used to infect HeLa-CD4 cells (clone H1-J) (13) that were pretreated with Polybrene (8 µg/ml; Sigma, St. Louis, Mo.) for 30 min at 37°C. The infected cells were seeded 48 h later in the presence of 40 µg of mycophenolic acid per ml, and the resistant colonies were fixed and stained 15 to 21 days later. We have obtained identical results in nine independent experiments, including the four representative studies summarized in Table 1. In all cases, the heterokaryons that contained the wild-type HIV gpt provirus produced much more infectious virus than the heterokaryons that contained the vif-deleted HIV gpt provirus. Indeed, the latter titers were zero in several experiments, and the average titers of wild-type virus in our nine independent experiments were approximately 20 times higher than the average titers of vif-deleted virus. This basic result was obtained regardless of whether the infectious virions were harvested at 24, 48, or 72 h after mixing of the HIV gpt-expressing H9 cells with the HeLa-tc-gp160 cells.
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We also attempted to perform this genetic complementation study in the reverse manner by expressing the HIV gpt provirus in HeLa-CD4 cells and the HXB2 env gene in H9 cells. Unfortunately, the H9 cells could be transfected only inefficiently, and we were unable to obtain significant numbers of syncytia in step 3 or significant amounts of rescued infectious virus in step 4. Even if more efficient transfection of H9 cells could be achieved, it is likely that the resulting cells with gp120-gp41 complexes would fuse not only with HeLa-CD4 cells but also with other CD4-positive H9 cells in cultures. Apoptotic changes within the transfected H9 cultures would also have been expected (17). For these reasons, we concluded that the simple inverse protocol was not technically feasible.
The simplest interpretation of these results is that nonpermissive H9 cells contain a potent inhibitor of infectious HIV-1 production and that this inhibitor is counteracted by the virus-encoded Vif protein. The alternative hypothesis, that permissive HeLa cells contain a permissivity factor that replaces the requirement for Vif, appears to be inconsistent with our results. Even if this putative factor were slowly acting or were incapable of repairing aberrant HIV-1 components that had been synthesized in H9 cells prior to heterokaryon formation, we would have expected to see a relatively enhanced titer of vif-deleted HIV gpt virus by 48 to 72 h after initiation of heterokaryon formation. However, the heterokaryons that contained the vif-deleted HIV gpt provirus did not slowly begin to produce infectious virus. Alternatively, it is conceivable that a putative permissivity factor of HeLa cells might become inactivated in heterokaryons. However, this seems very unlikely, because its function was not observed even at the initial stages of heterokaryon formation (Table 1).
Although the heterokaryons that express wild-type HIV gpt release many more infectious virions than the heterokaryons that express vif-deleted HIV gpt, the titers in these experiments were also quite low (Table 1). Indeed, these titers were generally only approximately 1 to 2% as high as the titers released in step 1 by the initially transfected COS-7 cells. This quantitative difference is reasonable in part because COS-7 cells express transfected plasmids that have the simian virus 40 origin very efficiently. Moreover, only small fractions of the H9 nuclei appeared to enter the heterokaryons in step 3, and the latter may produce virions inefficiently. In addition, the H9 and HeLa-tc-gp160 cells aggregated in the cocultures, and many aggregates lifted into the culture medium. It has been reported that CD4-positive lymphoid cells undergo degenerative changes including apoptosis in cultures with cells that express HIV-1 envelope glycoprotein (17). These morphological changes occurred equally in the cocultures that contained the wild-type and vif-deleted HIV gpt proviruses. For the same reasons, however, even trace amounts of H9 cell contamination with virus or transfected COS-7 cells in step 3 might distort the eventual results. Because COS-7 cells are fully permissive, as documented above, this factor would have contributed equally to the titers of the wild-type and vif-deleted viruses and could not have reproducibly given the results that we observed.
Based on these considerations, we conclude that nonpermissive human T lymphocytes contain an endogenous and potent inhibitor of HIV-1 production that is overcome by the virus-encoded Vif protein, and we infer that this inhibitor may also occur in other nonpermissive cells, including macrophages. It is ironic that this inhibitor is apparently present only in these natural targets for HIV-1 infection and that it is absent in other human cells. Thus, we propose that CD4-positive T lymphocytes and macrophages may have an endogenous intracellular capacity to block HIV-1 replication and to cure the disease but that this potent inhibitor is held in check by Vif. This conclusion is consistent with a recent report that the Vif proteins of HIV-1 and simian immunodeficiency virus from African green monkeys may be active only in CD4-positive T lymphocytes from the respective species (25). Moreover, these Vif proteins act in a cell-specific rather than in a virus-specific manner. These results imply that Vif neutralizes the inhibitory activity of a cellular factor that occurs in lymphocytes, in agreement with our results. Several viral proteins function to thwart the host immune system (6, 10, 23), to block apoptosis, or to extend cellular lifespans (15), but we are unaware of another viral protein that blocks an intracellular inhibitor of infectious virus production. Further work will be needed to determine whether this inhibitor damages the virions during assembly in producer cells or whether it is incorporated into the virions to block their infectivity in target cells. We are currently attempting to identify an endogenous inhibitor in nonpermissive human cells. The implication that Vif counteracts a potent inhibitor of HIV-1 replication suggests that it would be an exceptionally promising target for drug development.
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ACKNOWLEDGMENTS |
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This research was supported by NIH grant CA67358. N.M. is partially supported by an NIH predoctoral fellowship in molecular hematology and oncology (T32HL07781).
We thank Hermann Bujard (Universitat Heidelberg, Heidelberg, Germany) for the generous gift of pUHD10-3. We are especially grateful to our colleague Emily Platt for generously donating the H9-42 cells that were used in several experiments, and for providing advice for the construction of vif-deleted pHIV-gpt, and to Susan Kozak, Shawn Kuhmann, Ali Nouri, David Johnson, and Chetankumar Tailor for encouragement and helpful suggestions.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97201-3098. Phone: (503) 494-8442. Fax: (503) 494-8393. E-mail: kabat{at}ohsu.edu.
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Journal of Virology, December 1998, p. 10251-10255, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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