JOURNAL OF VIROLOGY, Oct. 2010, p. 10933–10936
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Vol. 84, No. 20
The Glycosylated Gag Protein of a Murine Leukemia Virus Inhibits
the Antiretroviral Function of APOBEC3?
Angelo Kolokithas, Kyle Rosenke, Frank Malik, Duncan Hendrick, Lukas Swanson,
Mario L. Santiago,† John L. Portis, Kim J. Hasenkrug, and Leonard H. Evans*
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of
Allergy and Infectious Diseases, Hamilton, Montana 59840
Received 11 May 2010/Accepted 22 July 2010
APOBEC proteins have evolved as innate defenses against retroviral infections. Human immunodeficiency
virus (HIV) encodes the Vif protein to evade human APOBEC3G; however, mouse retroviruses do not encode
a Vif homologue, and it has not been understood how they evade mouse APOBEC3. We report here a murine
leukemia virus (MuLV) that utilizes its glycosylated Gag protein (gGag) to evade APOBEC3. gGag is critical
for infection of in vitro cell lines in the presence of APOBEC3. Furthermore, a gGag-deficient virus restricted
for replication in wild-type mice replicates efficiently in APOBEC3 knockout mice, implying a novel role of
gGag in circumventing the action of APOBEC3 in vivo.
APOBEC3G (hA3G) in humans and its mouse orthologue,
APOBEC3 (mA3), act as potent innate defenses against ret-
roviral infection. Both proteins deaminate cytidine in single-
stranded DNA, ultimately resulting in hypermutation of newly
synthesized proviral DNA (6, 16), although additional deami-
nase-independent mechanisms of inhibition have been identi-
fied (2). Infectious exogenous retroviruses, including human
immunodeficiency virus (HIV) and murine leukemia viruses
(MuLVs), have evolved mechanisms to circumvent the action
of the APOBEC proteins (3, 6). HIV encodes the Vif protein,
which facilitates the rapid proteolysis of hA3G, while the
mechanism by which exogenous MuLVs evade the action of
mA3 is unknown (6).
Exogenous MuLVs, as well as some other gammaretrovi-
ruses, encode a glycosylated Gag protein (gGag) originating
from an alternate translation start site upstream of the methi-
onine start site of the Gag structural polyproteins (10, 17, 27).
gGag is synthesized at similar rates and levels as the structural
Gag polyprotein in MuLV-infected cells but is glycosylated and
undergoes distinct proteolytic processing (10, 12, 21). A car-
boxyl fragment of gGag is released from the cell, while an
amino fragment is incorporated into the plasma membrane as
a type 2 transmembrane protein (12, 25). The functions of
gGag remain unclear, but mutations that eliminate its synthesis
severely impede in vivo replication of the virus with little, if
any, effect on replication in fibroblastic cell lines (7, 19, 26).
APOBEC3 proteins are expressed in many tissues in vivo but
are poorly expressed in many in vitro cell lines (6), suggesting
a possible link between gGag expression and the evasion of
mA3 by MuLVs. These studies were undertaken to determine
if the expression of the gGag protein facilitated MuLV repli-
cation in the presence of mA3 in vitro and in vivo.
Efficient infection of mA3-expressing cells is dependent on
gGag. Several studies of the effects of mA3 proteins on virus
replication examined the infectivity of virions released from
cells transfected with cloned proviral DNA in the presence or
absence of mA3 (9, 16, 28). Such analyses do not test effects of
mA3 present in the cytoplasm of the cells on the infectivity
of MuLVs that have not been previously exposed to mA3.
To address this issue, we developed an NIH 3T3 cell line
(3T3) that expressed a hemagglutinin (HA)-tagged full-length
mA3 protein (3T3/mA3) corresponding to the BALB/c allele (4).
The infectivity of the two coisogenic MuLVs, CasFrKP (gGag?)
and CasFr-3 ? 4 (gGag?) (26), in 3T3 and 3T3/mA3 cells was
compared using mixtures of the viruses, each carrying a distinct
retroviral vector encoding either alkaline phosphatase (LAPSN)
or ?-galactosidase (G1n?gSvNa), as previously described (14).
Experiments were performed using both MuLV-vector combi-
nations. These analyses indicated that cellular mA3 exerted a
marked inhibitory effect on the infectivity of gGag?virus but
not on the gGag?virus (Fig. 1). Interestingly, it was recently
reported that infection by Moloney MuLV (M-MuLV) (20)
and mouse mammary tumor virus (22) was partially inhibited
by mA3 and that both virion and cellular mA3 contributed to
the inhibition. Furthermore, HIV has also been reported to be
inhibited by cytoplasmic hA3G (35).
It is somewhat surprising that cellular mA3 exerts a gGag-
dependent effect on infecting MuLVs. The low level of virion-
associated gGag may directly influence the action of cellular
mA3; however, virion gGag is likely associated with the viral
envelope as a type 2 transmembrane protein, and it is difficult
to envision how it might interact with cellular mA3. Alterna-
tively, the susceptibility of the gGag?MuLV to cellular mA3
may occur by an indirect mechanism. In this regard, it has been
reported that gGag is involved in virion release and that gGag?
M-MuLV exhibits an abnormal morphology during virion bud-
ding (19). It is conceivable that mature virions may also be
altered from an mA3-resistant to an mA3-susceptible pheno-
* Corresponding author. Mailing address: Laboratory of Persistent
Viral Diseases, Rocky Mountain Laboratories, National Institute of
Allergy and Infectious Diseases, Hamilton, MT 59840. Phone: (406)
363-9374. Fax: (406) 363-9286. E-mail: email@example.com.
† Present address: University of Colorado Denver, Research Com-
plex 2 Bldg, Room 11013, 12700 E 19th Avenue, Mail Stop B-168,
Aurora, CO 80045.
?Published ahead of print on 11 August 2010.
Both gGag?and gGag?MuLVs incorporate mA3 into prog-
eny virions. A number of studies have reported partial inhibi-
tion of ecotropic MuLVs as a result of incorporation of mA3
into progeny virions (16, 20, 28, 33). Indeed, it has been sug-
gested that MuLVs may evade the action of mA3 by exclusion
of the protein from virions, although there are conflicting ac-
counts regarding this matter (4, 8, 15, 16, 24, 28). To determine
if the presence of gGag influenced the incorporation of mA3,
virions were isolated by isopycnic gradient centrifugation (10)
from mA3 cells infected with gGag?or gGag?MuLVs and
examined by immunoblot analyses using monoclonal antibod-
ies directly conjugated to horseradish peroxidase. mA3 was
readily detected in both virus preparations, with no discernible
differences in the levels of virion incorporation in gGag?or
gGag?MuLVs (Fig. 2A). This result is in agreement with
other reports that have shown incorporation of mA3 into viri-
ons (4, 15, 24, 28). Furthermore, gGag was also found to be
incorporated into virions (Fig. 2B), consistent with an earlier
study (11). Thus, inhibition of mA3-mediated antiviral activity
by gGag does not occur simply by preventing incorporation of
mA3 into virions.
Virion-associated mA3 selectively inhibits gGag?MuLV in-
fectivity. To determine if virion-incorporated mA3 differen-
tially influenced gGag?and gGag?MuLVs, we examined the
infectivity of viruses released from 3T3/mA3 cells as well as
from 3T3 cells lacking mA3. Both cell lines were transduced
with the retroviral vector LAPSN, which encodes alkaline
phosphatase, to enable the quantification of progeny virus in-
fectivity in single-cycle assays as previously described (14).
Cells were infected with gGag?or gGag?MuLVs, and the
infectivity of released viruses was quantified by alkaline phos-
phatase as well as by focal immunofluorescence assays (31) on
mA3?/?Mus dunni cells. Infectivity was normalized to the
number of progeny virions released using a colorimetric re-
verse transcriptase assay (Roche). The retroviral vector assays
and the fluorescence assays closely paralleled one another, and
their results were combined (Fig. 2C). These analyses revealed
that the specific infectivity of gGag?virus released from 3T3/
mA3 cells was markedly decreased compared to that of gGag?
virus released from 3T3 cells. In contrast, no decrease in in-
fectivity was observed with the gGag?virus released from
3T3/mA3 cells compared to 3T3 cells (Fig. 2C). Experiments
using an M. dunni cell line expressing the mA3 protein to
assess the effects of cellular as well as virion-incorporated mA3
on the infectivity of gGag?and gGag?MuLVs yielded similar
results (data not shown).
Our analyses indicated that mA3 did not inhibit the gGag?
MuLV; however, a number of studies have reported partial to
marked inhibition of other MuLVs (16, 20, 28, 33), all of which
encode a gGag protein. A direct comparison of the inhibitory
effects of mA3 on M-MuLV and the ecotropic AKV MuLV
revealed that AKV was inhibited to a greater extent than
M-MuLV (16). Differences in the susceptibility of MuLVs to
inhibition by mA3 could reflect differences in the efficacy of
their respective gGags to counteract mA3. In this regard, a
FIG. 1. Effect of cellular mA3 on infection by gGag?and gGag?
MuLVs. 3T3 and 3T3/mA3 cells were infected with mixtures of
gGag?and gGag?viruses, each carrying a distinct retroviral vector
encoding either alkaline phosphatase (LAPSN) or ?-galactosidase
(G1n?gSvNa), and assayed by scoring the number of foci of cells
expressing the respective enzymes. The mixtures were adjusted to give
equivalent titers of alkaline phosphatase and ?-galactosidase on 3T3
cells. Infectivity was expressed as focus-forming units (FFU). Statistical
analysis was performed using the unpaired Student t test.
FIG. 2. Infectivity of virions released from 3T3 or 3T3/mA3 cells
infected with gGag?or gGag?MuLVs. Virions released from 3T3/
mA3 cells infected with gGag?or with gGag?MuLVs were analyzed
by immunoblotting for the presence of mA3 or gGag. (A) Immunoblot
analysis of gGag?virions, gGag?virions, and a 3T3/mA3 cellular
lysate for the presence of mA3 using a horseradish peroxidase (HRP)-
conjugated anti-HA antibody (clone 3F10; Roche). The 3T3/mA3 cel-
lular lysate was included to enable a size comparison of mA3 in the
cells to those in the virions. The blot was also developed with an
HRP-conjugated monoclonal antibody to p30 (MAb 18-7) (5) as a
loading control. Exposure times for detecting mA3 were approximately
10-fold longer than those for p30. (B) Immunoblot analysis of gGag?
or gGag?virions for the presence of gGag using an HRP-conjugated
anti-gGag antibody (11). The blot was subsequently stripped and de-
veloped with an HRP-conjugated monoclonal antibody to p30 as a
loading control. Exposure times for detection of gGag were approxi-
mately 20-fold longer than for p30. (C) 3T3 cells or 3T3/mA3 cells
harboring the retroviral vector LAPSN were infected with gGag?or
gGag?MuLVs. The cells were grown for 40 h, the medium was
changed, and the virus was harvested after an 8-h period. Infectivity
was assessed on uninfected M. dunni cells by alkaline phosphatase
assays for newly transduced target cells and by focal immunofluores-
cence assays using a monoclonal antibody specifically reactive to the
envelope proteins of the MuLVs. Infectivity titers, expressed as FFU,
were normalized to the number of virions by assessing reverse tran-
scriptase activity (RT). RT was expressed as the absorbance per ml at
405 nm. Statistical analysis was performed using the unpaired Student
10934 NOTESJ. VIROL.
comparison of the gGag sequences of M-MuLV and AKV
reveals extensive amino acid differences in their amino-termi-
nal fragments. Recent studies have also reported that mA3
inhibits the replication of xenotropic murine leukemia-like ret-
rovirus (XMRV) to a much greater extent than M-MuLV (13,
24). All XMRV isolates exhibit a termination codon in the
coding sequences of gGag, resulting in a truncation of the
protein immediately preceding the transmembrane region
(34), suggesting that the sensitivity of XMRV to mA3 may be
mA3-deficient mice support the replication of gGag?and
gGag?MuLVs. If mA3 restriction is a major factor influencing
in vivo replication of MuLVs and its action is sufficiently re-
pressed by gGag, it would be expected that mice lacking mA3
would be permissive to infection by both gGag?and gGag?
MuLVs. To examine this possibility, we determined the level of
replication of gGag?and gGag?MuLVs in mA3 knockout
mice (mA3?/?) and their wild-type counterparts (mA3?/?)
(29). Comparisons of the replication of gGag?and gGag?
MuLVs revealed a clear influence of 129/Ola mA3 on their
replication (Fig. 3A). In agreement with previous studies on
the replication of gGag-deficient mutants (7, 20, 26), the rep-
lication of the gGag?MuLV was severely restricted in normal
129/Ola mice. However, in 129/Ola mice lacking mA3, the
gGag?and gGag?MuLVs replicated to equally high levels.
These results indicate that the inability of the gGag?MuLV to
replicate efficiently in vivo is the result of mA3 expression.
C57BL/6 mice contain the FV-1ballele (32), whereas the
MuLVs used in this study are n-tropic. Thus, the levels of
replication of the MuLVs in C57BL/6 mice were much lower
than those in the 129/Ola mice, which contain the FV-1nrallele
(Fig. 3B) (32) (M. L. Santiago, unpublished results). Never-
theless, replication in these mice was sufficient to observe mA3
inhibition in a gGag-dependent manner. Levels of the gGag?
MuLV were restored to the levels observed with the gGag?
MuLV in C57BL/6 knockout mice lacking mA3. It is notewor-
thy that C57BL/6 mice predominantly express a splice variant
mA3 mRNA which lacks exon 5 (1, 23, 29), while 129/Ola mice
predominantly express a complete mA3 mRNA. Our results
indicate that the MuLV gGag studied here is able to suppress
the antiviral effect of both the full-length and exon 5-deleted
proteins and further substantiate the role of gGag as an an-
tagonist of the restriction factor.
The studies presented here provide at least partial answers
to two difficult questions in retrovirology: those of the function
of the gGag of MuLVs and the means by which MuLVs evade
the action of APOBEC3. Although gGag of exogenous MuLVs
carries out a function similar to that of the Vif protein of HIV,
further studies are required to determine similarities and
differences in their modes of action. Such studies are par-
ticularly relevant in light of recent reports indicating cross-
species retroviral infections from mice to humans (18,
This research was supported by the Intramural Research Program of
the NIH, NIAID.
Mice were treated in accordance with the regulations and guidelines
of the Animal Care and Use Committee of the National Institutes of
We thank Bruce Chesebro, Byron Caughey, Jay Carroll, Lara Myers,
and Amanda Duley for helpful discussions and Dan Littman for pro-
viding the plasmid encoding mA3.
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