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Journal of Virology, May 2000, p. 4891-4893, Vol. 74, No. 10
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Cell-Dependent Requirement of Human
Immunodeficiency Virus Type 1 gp41 Cytoplasmic Tail for Env
Incorporation into Virions
Hirofumi
Akari,
Tomoharu
Fukumori, and
Akio
Adachi*
Department of Virology, The University of
Tokushima School of Medicine, Tokushima 770-8503, Japan
Received 8 November 1999/Accepted 16 February 2000
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ABSTRACT |
Growth kinetics in lymphocytic H9 and M8166 cells of two mutants of
human immunodeficiency virus type 1 (HIV-1) with deleted gp41
cytoplasmic tails were examined. While the mutant viruses designated
CTdel-44 and CTdel-144 were able to grow in M8166 cells, they were
unable to grow in H9 cells. Transfection and single-round infectivity
assays demonstrated that they are defective in the early phase of viral
replication in H9 cells. Analysis of the mutant virions revealed
drastically reduced incorporation of Env gp120 (compared with the
incorporation of wild-type virions) in H9 cells but normal
incorporation in M8166 cells. These results indicate that the HIV-1
cytoplasmic tail of gp41 determines virus infectivity in a
cell-dependent manner by affecting incorporation of Env into virions
and suggest the involvement of a host cell factor(s) in the Env incorporation.
| |
TEXT |
The Env glycoprotein of human
immunodeficiency virus type 1 (HIV-1) consists of a complex of surface
subunit gp120 and transmembrane subunit gp41, which are proteolytic
products of the gp160 precursor encoded by the env gene. In
HIV-1 infection, the gp120-gp41 complex interacts with CD4 and a batch
of chemokine receptors, and a fusion peptide and an N-terminal
ectodomain of gp41 dissociated from gp120 promote fusion between viral
and target cell membranes (6). The gp41 comprises two other
functional domains, i.e., the transmembrane subunit and cytoplasmic
domains. The gp41 cytoplasmic tail (CT) regions of HIV-1 and the other
primate immunodeficiency viruses are unusually long compared with those
of the other retroviruses (11). The CT regions of HIV-1 and
HIV-2 are generally around 150 amino acid residues in length; in
contrast, those of avian and murine leukemia viruses are typically 20 to 30 residues long. The CT region of HIV-1 contains a number of
functional domains: a tyrosine-based motif in the N-terminus as a
signal for the sorting and trafficking of Env (4); two
amphipathic motifs, which form an alpha-helix and bind calmodulin
(15, 17) and which are responsible for induction of
apoptosis in cells (12); and a C-terminal region important
for viral infectivity and Env incorporation into virions (5, 7, 8,
10, 15, 18, 20). During our mutational analysis of the HIV-1
genome, we have noticed that some mutants, including those with altered
CTs, exhibit cell-dependent growth properties (2, 13,
16; our unpublished results). In this report, we have
biologically and biochemically characterized the CT mutants and
demonstrated that the gp41 CT is a critical determinant for producing
cell-dependent virion infectivity.
To obtain input viruses to determine growth potentials of CT mutants in
lymphocytic cells, HeLa cells were transfected with proviral DNA clones
by the calcium phosphate coprecipitation method, and
cell-free solutions of viruses were prepared 48 h posttransfection as previously described (1, 16). Proviral clones used
here were wild-type (wt) pNL432 (1), its CT mutants CTdel-44
(previously referred as pNL-Hp) (2) and CTdel-144 (a
generous gift of Eric Freed, National Institutes of Health [NIH])
(7), an env-negative mutant pNL-Kp
(2), and a vif-negative mutant pNL-Nd (2, 16). CTdel-44 and CTdel-144 lack 44 and 144 C-terminal amino acids of Env gp41, respectively. The vif mutant virus
NL-Nd, which displays a cell-dependent growth phenotype
(16), was used as a control. Lymphocytic H9 and M8166
cells are nonpermissive and permissive for the NL-Nd virus,
respectively. H9 and M8166 cells were infected with each virus and were
monitored for virus production in the culture supernatants by
32P-based reverse transcriptase (RT) assay (19).
As shown in Fig. 1, H9 cells were not
productively infected by NL-Nd, CTdel-44, or CTdel-144 virus. In
contrast, in M8166 cells, these viruses grew to various extents. While
wt and NL-Nd viruses grew in a similar manner, CTdel-44 and CTdel-144
viruses showed delayed growth kinetics. CTdel-144 grew especially
poorly. These results indicated that HIV-1 gp41 CT is essential for
virus replication in H9 cells but not in M8166 cells.
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FIG. 1.
Growth kinetics of wt and mutant viruses in H9 and M8166
cells. Viruses were prepared from HeLa cells transfected with pNL432
(WT), pNL-Nd (vif mutant [Nd]), CTdel-44, or CTdel-144.
Cells (106) were infected with 5 × 105 RT
units of viruses. RT production in the culture supernatants was
monitored at intervals.
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To determine which step of the viral replication cycle in H9 cells is
affected by the truncated gp41, pNL432, and pNL-Nd, CT mutants were
directly transfected into H9 cells by electroporation (3).
Levels of virus production in the culture supernatants at 24 h
postelectroporation were determined by Gag p24 enzyme-linked immunosorbent assay (ELISA) (Cellular Products, Buffalo, N.Y.). No
major difference in the p24 level was observed (Table
1), and it appeared that the late
replication phase of the CT mutants in H9 cells as monitored by virus
production (Gag p24) is normal. The single-round infectivity of the
viruses produced in H9 and M8166 cells was then examined by
multinuclear activation of galactosidase inhibitor (MAGI) assay
(14). As shown in Fig. 2,
CTdel-44, CTdel-144, and NL-Nd viruses produced in H9 cells
demonstrated reduced infectivity, while those obtained from M8166 cells
exhibited a level of infectivity comparable with that of wt virus. From
these results, it was concluded that the two CT mutant viruses produced
in H9 cells are defective in the early stage of viral replication cycle
and suggested that the virions of the CT mutants released from H9 cells
are abnormal.
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FIG. 2.
Infectivity of wt and mutant viruses. Single-round
infectivity of viruses derived from H9 and M8166 cells electroporated
with pNL432 (WT), pNL-Nd (vif mutant [Nd]), pNL-Kp
(env mutant [Kp]), CTdel-44 (44), or CTdel-144 (144) was
monitored by MAGI assay. Infectivity was determined by counting blue
foci of X-Gal-treated MAGI cells 2 days after inoculation of viruses.
Average and standard deviation of three independent experiments are
shown.
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To examine virion proteins of the CT mutants, viruses were harvested
from electroporated H9 and M8166 cells and were concentrated by
ultracentrifugation through 20% sucrose cushion at 20,000 × g for 2 h at 4°C (3). The prepared virion
lysates were then analyzed by Western blotting assay (3).
The lysates containing an equal amount of the viral antigen as judged
by p24 ELISA were subjected to electrophoresis through sodium dodecyl
sulfate gradient (4 to 20%) polyacrylamide gels. The separated
proteins were blotted onto nitrocellulose membranes, were treated with
antibodies to HIV-1 proteins, and were visualized by using an ECL
system (Amersham, Little Chalfont, Buckinghamshire, United Kingdom).
The antisera to Env gp160 and RT were provided by M. Page through the
AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH. The anti-p24/p55 Gag
monoclonal antibody was obtained from Cosmobio (Tokyo, Japan). As shown
in Fig. 3, the level of gp120 was much
lower in CTdel-44 and CTdel-144 virions from H9 cells than in wt and
NL-Nd virions, whereas the level was comparable in all M8166-derived
virions. Figure 3 also shows no obvious differences in the amounts of
Gag and RT or in the levels of their processing among the virions derived from H9 and M8166 cells. Protein profiles of wt and mutant virions prepared from transfected HeLa cells were similar to those of
virions from transfected M8166 cells (data not shown). To further address this issue, the expression of Env within cells electroporated with various clones was similarly monitored. As shown in Fig. 4, the expression level of Env was
comparable among clone-transfected H9 and M8166 cells. In addition,
syncytia formation was similarly observed in the H9 cells transfected
with the clones. This observation suggested that the precursor of the
mutant Env was processed into biologically active mature proteins and
that these proteins were expressed on the surface of the cells as
previously reported (9). These data indicated that CTdel-44
and CTdel-144 produced in H9 cells but not in M8166 cells are defective
for Env incorporation into virions.
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FIG. 3.
Analysis of virion proteins by Western blotting. The
lysates of virions prepared from H9 (A to C) and M8166 (D to F) cells
electroporated with pNL432 (WT), pNL-Nd (vif mutant [Nd]),
CTdel-44, CTdel-144, or pUC19 (control) were analyzed by Western
blotting with a sheep anti-Env gp160 antiserum (A and D), a mouse
anti-p24 monoclonal antibody (B and E), and a sheep anti-RT antiserum
(C and F).
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FIG. 4.
Analysis of viral proteins expressed in cells by Western
blotting. The lysates of H9 (A and B) and M8166 (C and D) cells
electroporated with pNL432 (WT), pNL-Nd (vif mutant [Nd]),
CTdel-44, CTdel-144, or pUC19 (control) were analyzed by Western
blotting with a sheep anti-Env gp160 antiserum (A and C) and a mouse
anti-p24 monoclonal antibody (B and D).
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|
The results presented here strongly suggest that HIV-1 gp41 CT plays a
critical role during virus assembly and entry in the virus replication
cycle in a cell-dependent way. The key finding is the
producer-cell-dependent role of the gp41 CT in Env incorporation into
virions (Fig. 3). In the absence of gp41 CT, HIV-1 virions produced in
certain cell types virtually lack Env gp120 and are defective for
initiating the next round of the virus replication cycle. In normal
virus assembly, functional association of an unknown cell factor(s)
with some domain in the C-terminal 44 amino acid residues of gp41 is important.
Although H9 and M8166 cells are nonpermissive and permissive,
respectively, for both of the vif and CT mutants, we have
recently demonstrated that the function of Vif is unrelated to Env
(3). Further study is needed to ascertain the molecular
basis for the cell-dependent functional role of HIV-1 gp41 CT, and the
identification of the cell factor(s) responsible for Env incorporation
is critically required.
| |
ACKNOWLEDGMENTS |
We thank Eric O. Freed for providing a plasmid clone. The antisera
to Env gp160 and RT (from M. Page) were obtained through the AIDS
Research and Reference Reagent Program, Division of AIDS, NIAID, NIH.
We also thank Kazuko Yoshida for editorial assistance.
This work was supported by grants-in-aid for AIDS research from the
Ministry of Education, Science, Sports, and Culture of Japan and from
the Ministry of Health and Welfare of Japan and by a grant-in-aid for
biomedical research from the Uehara Memorial Foundation.
| |
ADDENDUM |
While the manuscript was being reviewed, Murakami and Freed
published similar results (15a).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Virology, The University of Tokushima School of Medicine, 3 Kuramoto, Tokushima 770-8503, Japan. Phone: 81-88-633-7078. Fax: 81-88-633-7080. E-mail: adachi{at}basic.med.tokushima-u.ac.jp.
| |
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Journal of Virology, May 2000, p. 4891-4893, Vol. 74, No. 10
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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