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Journal of Virology, March 1999, p. 2537-2540, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Group D Adenoviruses Infect Primary Central Nervous
System Cells More Efficiently than Those from Group C
Miguel
Chillon,1
Assumpció
Bosch,2
Joseph
Zabner,2
Lane
Law,2
Donna
Armentano,3
Michael J.
Welsh,1,2 and
Beverly L.
Davidson2,*
The Department of Internal
Medicine,2
Howard Hughes Medical
Institute,1 University of Iowa, College of
Medicine, Iowa City, Iowa, and
Genzyme Corporation, Framingham,
Massachusetts3
Received 21 July 1998/Accepted 10 November 1998
 |
ABSTRACT |
Group C adenovirus-mediated gene transfer to central nervous system
cells is inefficient. We found that wild-type group D viruses, or
recombinant adenovirus type 2 (Ad2) (group C) modified to contain Ad17
(group D) fiber, were more efficient in infecting primary cultures of
neurons. Together with studies on primary vascular endothelial cells
and tissue culture cell lines, our results indicate that there is not a
universally applicable adenovirus serotype for use as a gene transfer vector.
| |
TEXT |
Gene transfer for the correction of
inborn errors of metabolism or neurodegenerative disease in the central
nervous system (CNS) has been accomplished with recombinant adenoviral
vectors (7, 9, 14, 25). However, high particle doses are
required for efficacy in mice and rats and for the infection of large
numbers of cells in monkeys (4, 7, 8, 10, 16). Moreover, the
delivery of a high particle load induces an immune response after in
vivo application (2, 5, 22). Thus, gene transfer to
brain tissues with adenovirus type 2 (Ad2) or Ad5 vectors is inefficient, as it is in endothelia, smooth muscle cells, and differentiated airway epithelia (12, 33, 34). Methods which improve the efficiency of adenovirus-mediated gene transfer to the CNS
could reduce the particle load required to achieve sufficient levels of
transduction. Improved efficiency could then reduce toxicity and
increase the therapeutic index.
The coxsackievirus B-adenovirus receptor and major histocompatibility
complex class I 
2 domain are recently identified cellular receptors
for Ad2 and Ad5 fiber (3, 19, 30), the only serotypes of
adenovirus thus far tested in brain tissues. The inefficiency of gene
transfer to brain tissue in vivo, and to CNS cells in culture, could be
due to a lack of specific receptors for Ad5 fiber, similar to what was
found in adenovirus-mediated gene transfer to differentiated human
airway epithelia (24, 34). We hypothesized that gene
transfer to CNS cells could be enhanced by circumventing the
requirement for interaction between Ad5 fibers and Ad5 receptors.
One strategy to accomplish fiber-independent transduction of cells used
complexes of adenoviruses with lipids or polymers. Fasbender and
colleagues showed that mixing poly-L-lysine or cationic lipids with adenovirus prior to application enhanced gene transfer into
cells which were refractory to adenovirus-mediated gene transfer (12). In a different approach, bispecific antibodies or
modified fiber knob sequences were used to redirect the binding of
adenoviruses to different cellular receptors (11, 21, 28,
33).
As an alternative to altering the native tropisms of Ad2 and Ad5, we
hypothesized that other naturally occurring adenoviruses could possess
fibers or other capsid proteins which would direct improved infection
efficiency in brain cells. We tested the ability of different
adenoviral serotypes, representative of groups A to F, to infect
primary CNS cell cultures. Our results suggest that adenovirus vectors
containing Ad17 fiber may be more appropriate vectors for infection of
CNS cells in particular, as well as other primary cells.
Comparative analysis of adenoviral serotypes.
Fetal rat CNS
cells were isolated from the upper layer of the cortex of D16-17 rat
fetuses, seeded onto collagen-coated plates, and cultured in Eagle's
minimal essential medium (MEM) supplemented with 10% fetal bovine
serum, 30 mM dextrose, 2 mM L-glutamine, and 20 mM KCl.
Cultures were maintained for 2 to 3 days prior to adenovirus
application. Cultures contained more than 90% neuronal cells
(17) based on immunohistochemistry assays (data not shown). Wild-type virus lysates were purchased from the American Type Culture
Collection, propagated in 293 cells in Dulbecco's MEM supplemented
with fetal bovine serum, 10% and purified by standard methods
(10). Titers (in PFU per milliliter) were determined by end
point dilution as previously described (18, 26) except that
viruses were incubated for 3 days rather than 30 min. Purified viruses
were placed onto primary neuronal cultures at a multiplicity of
infection (MOI) of 50 PFU/cell for 30 min, and infection was monitored
by immunohistochemistry for hexon production after 48 h. Briefly,
cells were fixed with acetone-methanol 48 h after infection,
followed by the addition of polyclonal fluorescein isothiocyanate-labeled antihexon antibody (Chemicon International Inc., Temecula, Calif.). Hexon-positive cells were counted by using
low-magnification fluorescence photomicrographs of the monolayers (Leitz MZWild fluorescent photomicroscope). The following serotypes from all six groups of adenovirus were tested: 31 (group A); 3, 7, and
14 (group B); 2 and 5 (group C); 9, 17, 19, 26, and 30 (group D); 4 (group E); and 41 (group F).
The results, summarized in Table 1,
demonstrated that serotypes from groups A and B infected only 5% of
cells. Interestingly, group C viruses, which are currently the most
commonly used backbone for gene transfer to animals and humans, also
showed minimal infection. We found that viruses from groups D, E, and F
were the most transfer efficient, with 20 to 60% of the cells in
neuronal cultures testing positive for hexon production.
To test if the improved infection noted after application of groups D,
E, and F serotypes was a general phenomenon, we did
similar
experiments on primary vascular endothelial cell cultures
(Table
1).
Human umbilical vein endothelial cells (HUVEC) were
harvested and
cultured in M199 medium supplemented with 1%
L-glutamine,
basal medium Eagle vitamin solution, and basal medium Eagle amino
acids. Again, all serotypes were applied at an MOI of 50 for 30
min. Unlike primary neuronal cultures, HUVEC were infected most
efficiently by group B in addition to group D viruses. Serotypes
from
groups E and F showed very low to no evidence of infection
under these
conditions, as did viruses from groups A and
C.
Infection of primary CNS cell cultures with Ad2
gal2(17f) and
Ad2gal2.
The cellular attachment of adenovirus is mediated
primarily through fiber. Therefore, we next tested whether fiber 17 sequences were responsible for the increased rate of infection. To
determine this, a chimeric Ad2-Ad17 virus was generated (Fig.
1). The plasmid pAdORF6 (1)
was cut with NdeI and BamHI to remove the Ad2
fiber-coding and polyadenylation signal sequences (bp 31076 to 32815).
An NdeI-BamHI fragment containing the Ad17
fiber-coding sequence (bp 30983 to 32035) was generated by PCR and
ligated along with simian virus 40 polyadenylation signal into
NdeI-BamHI-cut pAdORF6 to generate pAdORF6fiber17. This plasmid was cut with PacI and ligated
to PacI-cut Ad2gal2 (1) genomic DNA to
generate Ad2gal2(17f). Ligated DNAs were transfected into 293 cells
to generate the Ad2gal2(17f) virus. Plaques were isolated and
expanded, and Hirt DNAs were analyzed by NdeI and
XbaI restriction to confirm the structure of the virus. The
chimeric virus is similar to Ad2gal2 (1) except that the
Ad2 fiber sequences from bp 20624 to 32815 have been deleted and
replaced with those from Ad17.
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FIG. 1.
Schematic representation of the construction of Ad2
virus containing Ad17 fiber sequences. The final construct contains Ad2
backbone sequences with all but the first 17 amino acids of the fiber
molecule removed. Replaced in frame is the Ad17 fiber from amino acid
18 to the COOH terminus. A simian virus 40 (SV40) polyadenylation
signal was added to the 3' end of the fiber sequence as indicated. The
E4 ORF6 sequences are indicated for orientation. CMV, cytomegalovirus;
-gal, -galactosidase; MLT, major late transcription.
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|
Cultured primary cells from fetal rat cortex were infected at an MOI of
10 with Ad2
gal2 or Ad2
gal2(17f), and
-galactosidase
activity
was assessed initially by histochemical staining. Figure
2A shows a representative example of the
differences in both the
numbers of cells infected and the relative
levels of enzyme expression
following Ad2
gal2(17f)- and
Ad2
gal2-mediated gene transfer.
In parallel studies,
-galactosidase activity was assayed with
a Galacto-Lite kit (Tropix,
Inc., Bedford, Mass.) and a luminometer
(Monolight 2010; Analytical
Luminescence Laboratory, San Diego,
Calif.) according to the
manufacturers' recommendations and normalized
to total protein
concentration (protein assay reagent; Bio-Rad
Laboratories, Hercules,
Calif.).
-Galactosidase activity assays
after Ad2
gal2(17f)
infection showed that it is approximately
sevenfold more efficient than
Ad2
gal2 (Fig.
2B).
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FIG. 2.
Transgene expression after Ad2gal2(17f) and
Ad2gal2 infection of primary cortical cultures. Cells were infected
at an MOI of 10 for 2 h at 37°C, virus solution was removed, and
cells were cultured in standard media for an additional 48 h. (A)
-Galactosidase histochemistry; (B) -galactosidase activity assay.
LU, relative light units. Data represent averages ± standard
errors of the means.
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|
To further enrich for neurons, some cultures were treated with cytosine
-
D-arabinofuranoside (
17). Treatment of
cultures
with cytosine
-
D-arabinofuranoside did not
significantly reduce
the levels of total enzyme activity, reflecting
the fact that
the cultures contained mostly neuronal cells (data not
shown).
Nonetheless, combined X-Gal
(5-bromo-4-chloro-3-indolyl-
-
D-galactopyranoside)
histochemistry and immunohistochemical staining for astrocytes
(mouse
anti-glial fibrillary acidic protein; Biogenix, San Ramon,
Calif.) and
oligodendroglia (mouse anti-myelin/oligodendrocyte
monoclonal antibody;
Chemicon) followed by incubation in secondary
antibodies conjugated to
horseradish peroxidase and horseradish
peroxidase substrate (Vector
Labs, Burlingame, Calif.) indicated
that glia were also capable of
being infected with Ad2
gal2(17f)
(Fig.
3). There was no obvious preference for
oligodendroglia
or astrocytes in these culture conditions. Together,
these results
demonstrate that Ad17 fiber does not direct infection
specifically
to neurons.
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FIG. 3.
Colocalization of -galactosidase activity and
cell-specific markers. Primary cortical cultures were infected with
Ad2gal2(17f) or Ad2gal2 as described for Fig. 2. Two days
after infection cells were histochemically stained for
-galactosidase followed by immunostaining with antibodies specific
for astrocytes (glial fibrillary acidic protein [GFAP]) and
oligodendrocytes (OLIGO). The photographs are selective and do not
represent the cultures in general, which contained more than 90%
neurons (17).
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|
We also compared infection of Ad2
gal2(17f) to Ad2
gal2 in cultures
of HUVEC and three cell lines (NIH 3T3, HeLa, and HEK293).
NIH3T3 and
HEK293 cells were cultured on 96-well plates in Dulbecco's
MEM
(high glucose) supplemented with 10% fetal calf serum. HeLa
cells
were cultured on 96-well plates in Eagle's MEM supplemented
with
10% fetal calf serum and 10 mM nonessential amino acids.
Figure
4 shows that Ad2
gal2(17f) was 21-fold
more efficient than
Ad2
gal2 as a gene transfer vector in HUVEC.
However, Ad2
gal2(17f)
was either equivalent (in NIH 3T3 cells) or
less efficient (in
HEK293 and HeLa cells) at infecting the cell lines
tested. Collectively,
the data suggest that the increased
infection efficiencies observed
with wild-type Ad17 and
Ad2
gal2(17f) viruses could be attributed,
in part, to properties of
the Ad17 fiber.
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FIG. 4.
-Galactosidase activity in primary vascular
endothelia or various cell lines infected with Ad2gal2(17f) or
Ad2gal2 (MOI = 50). Data represent averages ± standard
errors of the means. RLU, relative light units.
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|
Various serotypes of human adenovirus show specific tissue tropisms and
infect different cells (
20). However, only group
C
adenoviruses have been used as vectors for gene transfer. Thus,
the
current approach to adenovirus-mediated gene transfer has
followed
a "one-size-fits-all" strategy. Because gene transfer
to brain
tissue by Ad5 is not optimal, we tested the hypothesis
that different
serotypes might be more
efficient.
The screening of 12 different serotypes from groups A to F on primary
cerebral cortical cells isolated from fetal rats showed
that group D
adenoviruses were most infectious, with the other
groups following in
the order F > E > C, A, and B. Our results
with primary rat
neuronal cells may not necessarily reflect which
serotype is most
efficient for primate brain tissue. Similarly,
the improved tropism for
primary vascular endothelia of group
D compared with group C viruses
may not be characteristic of endothelia
in general. However, our
studies on primary cells, together with
our observations that Ad2 and
Ad5 were more efficient than the
chimeric viruses for infection of the
tissue culture cell lines
tested, suggest that there could be a wide
variation in receptors
capable of mediating adenovirus uptake in
different cell types,
and in different
species.
Adenovirus fiber binds to cellular receptors initiating infection, and
altering the fiber's moieties can change its natural
tropism (
3,
13,
15,
21,
29). In addition to increased
infection of group D
serotypes of primary rat neuronal cells and
human vascular endothelia,
we noted improved gene transfer efficiency
with a recombinant
Ad2
gal2(17f) chimera. This virus differs from
the parental Ad2-based
vector only in its fiber region. Together,
the data suggest that Ad17
fiber is in part responsible for the
improved
infection.
Studies have also demonstrated the importance of integrins on the
host cell surface in adenovirus infection; both
v3 and
v5
mediate internalization of the virus in tissue culture cell
lines
through interaction with the penton base proteins (
31,
32).
In addition to its interactions with fiber, increased efficiency
of
gene transfer with Ad2
gal2(17f) may be partially attributable
to
improved interaction of cell surface integrins with Ad2 penton
base.
The Ad17 fiber is 116 amino acids smaller than Ad2 and is
approximately
one-third shorter in the shaft region. As has been
suggested for Ad9
(
27), the short shaft length may allow capsid
proteins to
come into close association with the cell surface,
facilitating
entry.
In summary, viruses modified to contain Ad17 fiber appear to be better
vectors for gene transfer to CNS cells, suggesting
that they could be
used at lower titers both in culture and in
vivo. With lower doses
applied, direct cellular toxicity could
be reduced and in vivo immune
responses may be attenuated (
6).
In brain tissue, this could
translate to extended expression,
particularly in the case of
nonimmunogenic transgenes (
23).
Nucleotide sequence accession number.
The sequence of bp 31001 to 32053 of Ad17 has been deposited in GenBank by D. Armentano under
accession no. AF108105.
| |
ACKNOWLEDGMENTS |
We acknowledge Richard Anderson and the University of Iowa Gene
Transfer Vector Core for help with vectors.
This work was supported in part by the NIH grants HD33531 and NS34568
and the Roy J. Carver Trust.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: 200 EMRB,
University of Iowa, Iowa City, IA 52242. Phone: (319) 353-5511. Fax:
(319) 335-7623. E-mail: beverly-davidson{at}uiowa.edu.
| |
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Journal of Virology, March 1999, p. 2537-2540, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Wohlfahrt, M. E., Beard, B. C., Lieber, A., Kiem, H.-P.
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