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Journal of Virology, September 2001, p. 8016-8020, Vol. 75, No. 17
Department of Microbiology, Immunology and
Molecular Genetics1 Department of
Medicine,2 and UCLA AIDS
Institute,3 UCLA School of Medicine, Los
Angeles, California 90095
Received 19 January 2001/Accepted 4 June 2001
Targeted stable transduction of specific cells is a
highly desirable goal for gene therapy applications. We report an
efficient and broadly applicable approach for targeting retroviral
vectors to specific cells. We find that the envelope of the alphavirus Sindbis virus can pseudotype human immunodeficiency virus type 1- and murine leukemia virus-based retroviral vectors. When
modified to contain the Fc-binding domain of protein A, this envelope
gives a significant enhancement in specificity in combination with
antibodies specific for HLA and CD4 relative to that without antibody.
Unlike previous targeting strategies for retroviral transduction,
the virus titers are relatively high and stable and can be further increased by ultracentrifugation. This study provides proof
of principle for a targeting strategy that would be generally useful for many gene therapy applications.
Efficient targeting of specific
cells to achieve stable transduction has been attempted by various
strategies. Inserting ligands or single-chain antibodies into the
retroviral receptor binding envelope subunit has been the most common
approach used to alter and/or restrict the host range of retroviral
vectors (1, 5, 7, 8, 13, 14, 17, 24-26). Bridging virus
vector and cell by antibodies or ligands is another approach (3,
20). In general, most strategies have suffered from inconsistent
specificity and low viral titers as a result of modification of the
retroviral envelope (1, 5, 9, 13, 17, 24-26). The
modified envelope proteins appear to have specific binding activity but
have low fusion activity (14, 28), resulting in
inefficient entry into cells.
The alphavirus Sindbis virus encodes two transmembrane envelope
proteins, E1 and E2. E2 is responsible for receptor binding; E1 is
responsible for pH-dependent fusion. Unlike retroviruses, the Sindbis
virus fusogenic E1 protein can fuse to cells independently of the
receptor binding E2 protein (23). Recently, vectors based upon the Sindbis virus RNA genome were constructed whereby the Sindbis
virus E2 envelope protein was modified by insertion of an Fc-binding
portion (ZZ domain) (12) of protein A (6,
18). These Sindbis virus vectors would bind to and enter cells
bearing specific cell surface antigens only in the presence of the
appropriate monoclonal antibody (MAb). However, as a lytic RNA virus,
Sindbis virus is not suitable for applications requiring stable
transduction (6, 21). We tested the possibility that
human immunodeficiency virus type 1 (HIV-1)-based vectors could
potentially be pseudotyped with Sindbis virus envelope, thereby
conferring the targeting properties of the modified Sindbis virus
envelope to the HIV-1 vector.
Plasmid construction.
The expression vector of Sindbis virus
envelope protein, plntron SINDBIS, was made by cloning Sindbis virus
envelope into pHCMV G (27), replacing the vesicular
stomatitis virus G protein. The Sindbis virus envelope fragment was
derived from the plasmid TOTO 2000 (kindly provided by Henry Huang).
The envelope region of TOTO 2000 was derived from TOTO 1000 (19). The expression vector of the fusion protein, plntron
ZZ SINDBIS, was derived from plntron SINDBIS and pEZZ 18 (Pharmacia
Biotech). First, a BstEII site was introduced into plntron
SINDBIS between the codons for amino acids 71 and 74 of the E2
glycoprotein as described before (18) by PCR-based
mutagenesis, and the resulting construct was designated plntron Bst
SINDBIS. A sequence corresponding to the region of protein A containing
two synthetic immunoglobulin G (IgG) binding domains (ZZ domain) was
amplified by PCR using pEZZ 18 as the template and cloned into the
BstEII site of plntron Bst SINDBIS, and the resulting
construct was designated plntron ZZ SINDBIS.
Cell lines.
HLtat CD4 cells were generated by cotransfection
of CDM8CD4 (4) and pPUR (Clontech) into HLtat cells (NIH
AIDS Research and Reference Reagent Program). Briefly, HLtat cells were
plated the day prior to transfection at a density of 2 × 106/well in a six-well plate. Cells were cotransfected with
20 µg of CDM8CD4 and 1 µg of pPUR using Lipofectin (Gibco BRL,
Grand Island, N.Y.) according to the manufacturer's instructions. Two days posttransfection, cells were trypsinized and cultured in 96-well
plates at a density of 0.1 cells/well with Dulbecco modified Eagle
medium (DMEM) supplemented with 10% calf serum, 100 U of penicillin/ml, 100 µg of streptomycin/ml, and 1 mg of puromycin/ml. Two weeks after the transfection, the puromycin-resistant clones were
stained with anti-CD4-fluorescein isothiocyanate at 4°C for 30 min
and washed twice with fluorescence-activated cell sorting (FACS) buffer
(phosphate-buffered saline plus 2% fetal calf serum). CD4 expression
was analyzed by flow cytometry, and the clone with the highest
expression of CD4 (clone 18) was designated HLtat CD4 cells. HLtat
cells and HLtat CD4 cells were maintained in DMEM with 10% fetal calf
serum, 100 U of penicillin/ml, and 100 µg of streptomycin/ml.
Vector production.
SINDBIS- or ZZ SINDBIS-pseudotyped
lentivirus vectors expressing the luciferase reporter gene were
produced by calcium phosphate-mediated transfection of 293T cells as
described previously (2). 293T cells (2 × 107) were transfected with 12.5 µg of pCMVdR8.2DVPR
(2), 12.5 µg of the lentivirus reporter vector pHRCMVLuc
(16), and 5 µg of the envelope protein expression vector
(plntron SINDBIS or plntron ZZ SINDBIS). For generation of ZZ
SINDBIS-pseudotyped lentivirus vectors expressing the enhanced green
fluorescent protein (EGFP) reporter gene, 5 µg of plntron SINDBIS ZZ,
12.5 µg of pCMVdR8.2DVPR (2), and 12.5 µg of the
lentivirus reporter vector pHRCMV EGFP (10) or
pCS-Rh-MLV-E (10) were used. For the generation of ZZ
SINDBIS-pseudotyped murine leukemia virus vector, 5 µg of plntron SINDBIS ZZ, 12.5 µg of pSV
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.17.8016-8020.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Antibody-Directed Targeting of Retroviral Vectors
via Cell Surface Antigens
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
envMLV
(10), and 12.5 µg of pSR
LEGFP (10) were
used. 293T cells were cultured in DMEM with 10% ultra-low-IgG fetal
bovine serum (Gibco BRL), 100 U of penicillin/ml, and 100 µg of
streptomycin/ml. Supernatants were collected on days 2 and 3 posttransfection and filtered through a 0.22-µm-pore-size filter;
stocks were maintained at 
70°C.
LEGFP (ZZ SINDBIS) (100× concentrated) with
anti-human leukocyte antigen class I molecules A, B, and C (HLA ABC) (1 µg/ml) for 2 h at 37°C in 5% CO2. The virus was
removed, and cells were cultured in DMEM with 10% calf serum, 100 U of
penicillin/ml, and 100 µg of streptomycin/ml. Three days
postinfection, the cells were analyzed for EGFP expression by flow cytometry.
MAbs. Anti-HLA ABC was purchased from Sigma (St. Louis, Mo.). Anti-CD4 used for targeting was produced by the hybridoma OKT4 (ATCC CRL8002) and purified by protein A (Pierce, Rockford, Ill.). Conjugated anti-CD4 antibodies (phycoerythrin [PE] or fluorescein isothiocyanate) that recognize a CD4 epitope different from OKT4 were purchased from Becton Dickinson (San Jose, Calif.). For targeting, antibodies were selected from the IgG subclasses that are known to bind protein A.
Infection by luciferase vectors. SINDBIS or ZZ SINDBIS-pseudotyped HIV-1 vectors HRCMVLuc (SINDBIS) and HRCMVLuc (ZZ SINDBIS) were incubated with anti-HLA ABC at various concentrations for 1 h on ice prior to the infection. 293T cells (2 × 105) or BHK cells (6 × 104) were infected with these vectors with or without MAb for 2 h at 37°C with 5% CO2. The vectors were subsequently removed and replaced with 1 ml of DMEM with 10% calf serum, 100 U of penicillin/ml, and 100 µg of streptomycin/ml. Four days postinfection, 293T cells (1 × 105) or BHK cells (5 × 105) were lysed in 200 µl of cell culture lysis reagent (Promega Corp., Madison, Wis.). The lysate was centrifuged to remove nuclei. The supernatant (20 µl) was analyzed for luciferase activity as described before (15).
Infection of mixed culture of HLtat cells and HLtat CD4 cells. HRCMVEGFP (ZZ SINDBIS) was incubated with anti-CD4 (1 µg/ml) or anti-HLA (1 µg/ml) for 1 h on ice prior to infection. The mixed culture of HLtat cells and HLtat CD4 cells was infected with HRCMVEGFP (ZZ SINDBIS) with or without the MAb for 2 h at 37°C with 5% CO2. The virus was subsequently removed and replaced with 1 ml of fresh medium.
The mixture of HLtat cells and HLtat CD4 cells was detached by 2 mM EDTA-phosphate-buffered saline 3 days postinfection. The cells (2 × 105) were stained with 50 µl of anti-CD4-PE (5 µg/ml) for 30 min on ice. The cells were then washed with FACS buffer and analyzed by flow cytometry.Infection of PBMC. Preparation of peripheral blood mononuclear cells (PBMC) and stimulation of them by anti-CD3 MAb and anti-CD28 MAb were done as previously described (10). In brief, PBMC were activated by anti-CD3 and anti-CD28 antibodies for 2 days. After activation by the antibodies, PBMC were cultured for 1 day in growth medium (RPMI 1640 supplemented with 10% fetal bovine serum, 100 U of penicillin/ml, 100 µg of streptomycin/ml, and 1 mg of interleukin 2/ml) in the absence of the antibodies.
CS-Rh-MLV-E (ZZ SINDBIS) was incubated with anti-CD4 (10 µg/ml) or anti-HLA (10 µg/ml) for 1 h on ice prior to the infection. CD3- and CD28-activated PBMC (105) were infected with the vector with or without MAb for 2 h at 37°C with 5% CO2. The vector was subsequently removed and replaced with 1 ml of growth medium. Three days postinfection, the PBMC (2 × 105) were stained with 50 µl of anti-CD4-PE (5 µg/ml) for 30 min on ice. The cells were then washed with FACS buffer and analyzed by flow cytometry.Immunoblot assay. HIV vector (HRCMVEGFP) with no envelope, pseudotyped with Sindbis virus envelope, or pseudotyped with ZZ SINDBIS was concentrated by ultracentrifugation and resuspended in electrophoresis loading buffer (20% glycerol, 10% 2-mercaptoethanol, 4% sodium dodecyl sulfate [SDS] 125 mM Tris-HCl [pH 6.8], 0.02% bromophenol blue) and boiled for 5 min. The amount of viral sample was normalized to the amount of HIV p24 (90 ng of p24/sample). The samples were subjected to electrophoresis through an SDS-10% polyacrylamide gel as described previously (15). Immunoblot analysis was performed with anti-Sindbis virus ascitic fluid (ATCC VR-1248) and horseradish peroxidase-conjugated anti-mouse antibody (Santa Cruz Biotechnology, Santa Cruz, Calif.). The protein bands were visualized by enhanced chemiluminescence (Amersham, Piscataway, N.J.).
Flow cytometry. Flow cytometry was performed with a FACScan flow cytometer (Becton Dickinson). The data were analyzed with the Cell Quest program (Becton Dickinson).
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RESULTS AND DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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We first tested whether the wild-type Sindbis virus envelope would
pseudotype with HIV-1. The Sindbis virus envelope proteins were
expressed in a DNA-based vector using the cytomegalovirus immediate
early promoter (Fig. 1). We produced
HIV-1 vectors bearing luciferase reporter genes encoding wild-type
Sindbis virus envelope [HRCMVLuc (SINDBIS)] via cotransfection of
293T cells. The resulting virus was used to infect human 293T and
hamster BHK cells (Fig. 2). These results
demonstrate that the wild-type Sindbis virus envelope forms
pseudotypes with HIV-1 efficiently.
|
-globin gene. p(A), polyadenylation
signal.
|
We modified the Sindbis envelope in an analogous fashion to that previously described (18) by inserting the IgG binding region of protein A (ZZ domain) into the E2 envelope protein at the receptor binding domain (Fig. 1). In the absence of antibody, the HIV-1 vector (HRCMVLuc) bearing the modified Sindbis virus envelope (ZZ SINDBIS) showed substantially lower levels of luciferase activity than wild-type Sindbis virus envelope, although still higher than background levels. In the presence of antibodies directed against HLA ABC, the levels of infection increased up to over a 30-fold enhancement over those obtained without antibody and to levels comparable to those obtained with wild-type Sindbis envelope (Fig. 2). As a control, no augmentation in infectivity was observed with BHK rodent cells, which do not bear HLA antigens.
We investigated incorporation of Sindbis virus envelope and ZZ SINDBIS
into the HIV-1 vector. Pseudotyped virions were subjected to Western
blotting and probed using a mouse anti-Sindbis virus antibody that
detects E2 protein (Fig. 3). This
polyclonal antibody was generated by immunization of mice with Sindbis
virus (ATCC VR-1248). HRCMVEGFP (SINDBIS) showed a 50- to 55-kDa band
corresponding to the E2 protein, and HRCMVEGFP (ZZ SINDBIS) showed a
major band around 65 kDa, which is the estimated molecular mass of the
chimeric protein (Fig. 3). Consistent with a previous report
(18), the E1 protein is not detected using this
anti-Sindbis virus antibody.
|
Of practical importance for gene therapy applications, the titers of
HIV-1 vector bearing ZZ SINDBIS [HRCMVLuc (ZZ SINDBIS)] were stable
over at least two freeze-thaw cycles in which the vector was frozen at
70°C for 2 to 4 h and thawed in a 37°C water bath. Virus
recovery was 103% and 115% of titers of untreated virus after one and
two freeze- thaw cycles, respectively. These viruses could also be
concentrated at least 100-fold by ultracentrifugation without loss of
infectivity: the titer of 2 µl of 100×-concentrated virus was
2.2 × 107 EGFP transduction units/ml, or 96% of the
titer of unconcentrated virus (2.3 × 105 EGFP
transduction units/ml).
Targeting efficiencies were similar when HRCMVEGFP (ZZ SINDBIS) was concentrated after incubation of antibody with virus (30 min at 25°C) and when it was concentrated before addition of antibody (data not shown). As expected, no targeting was observed when wild-type Sindbis virus envelope was concentrated in the presence of antibody. This result also demonstrates stable binding of antibody to the HRCMVEGFP (ZZ SINDBIS) virions.
More quantitative data on efficiencies of transduction were derived by
the use of an HIV-1 vector bearing the EGFP gene as a reporter gene
that allows detection and enumeration by flow cytometry. Virus stocks
in the absence of concentration were about 1 × 105 to
3 × 105 EGFP+ units/ml on 293T cells
[HRCMVEGFP (ZZ SINDBIS), in the presence of anti-HLA antibody and as
determined by flow cytometry]. Consistent with our initial results
utilizing the luciferase gene as a reporter gene, the EGFP-based HIV-1
vector specifically infected human cells that bear HLA molecules in the
presence of anti-HLA ABC antibodies (Fig.
4A). Since the efficiency of
pseudotyping depends upon the retroviral species, we also
tested the ability of the Sindbis virus envelope to
pseudotype with murine retroviruses. We utilized the murine
retroviral vector SRLEGFP to assess targeting to HLA. We found
that SRLEGFP (ZZ SINDBIS) transduced human cells efficiently
only in the presence of anti-HLA (Fig. 4B). With both HIV-1 and murine
vectors, addition of the reverse transcriptase inhibitors zidovudine
and nevirapine blocked the infection (data not shown), substantiating
the idea that expression of EGFP is a result of a normal retroviral
infection process and not due to reported
"pseudotransduction" of EGFP protein derived from producer
cells (11).
|
We demonstrated targeting in heterogeneous cell populations. A mixed
culture of HLtat cells and HLtat CD4 cells was infected with HRCMVEGFP
(ZZ SINDBIS) either alone or with anti-CD4 antibody (Fig.
5). Virus with anti-CD4 antibody resulted
in preferential infection of HLtat CD4 cells. As a control, virus
treated with antibody directed against HLA ABC present on both HLtat
cells and HLtat CD4 cells allowed efficient transduction but did not confer preferential transduction of either population.
|
Human primary PBMC consist of both CD4+ and
CD4 subpopulations. We determined whether we could
specifically target the CD4-positive population of lymphocytes by using
an anti-CD4 MAb (Fig. 5). The HIV vector (CS-Rh-MLVE)
pseudotyped by ZZ SINDBIS pretreated with anti-CD4 antibody
resulted in preferential infection of the CD4-positive subpopulation.
As a control, antibody directed against HLA ABC present on both
CD4+ and CD4 subpopulations did not confer
preferential transduction of either CD4+ or
CD4 subpopulations of cells.
The approach described here for specific targeting of cells by retroviral vector transduction overcomes many of the limitations of previous targeting strategies. The preparation of targeting vector is not limited by the introduction of modifications into native retroviral envelopes that usually result in substantial decreases in infectivity. This strategy is applicable to both lentivirus and murine retroviral vectors. The Sindbis virus pseudotyped virions can be produced at relatively high titers and are also highly stable to ultracentrifugation and freeze-thaw cycles, thus facilitating the enhancement of titers and storage. Finally, the approach described here should in theory be generally applicable to any cell surface molecule for which there are specific reagents that bind. MAbs were used here; however, other applications could involve ligands for specific receptors, peptides, or nucleic acid reagents selected for specific binding properties. Depending on the particular application, the Sindbis virus E2 protein could be modified to directly encode the ligand (21) and/or include other affinity reagents, such as streptavidin. Such reagents would be more amenable to in vivo applications where the presence of plasma antibodies would complicate use of the chimeric ZZ domain.
The development of specific targeting reagents for stable gene transfer raises a number of possible applications which were not previously available. For example, current hematopoietic stem cell gene transfer experiments utilize amphotropic and vesicular stomatitis virus G-pseudotyped murine or lentiviral vectors to infect hematopoietic stem cells. These studies require technically demanding and expensive procedures to purify CD34+ cells and transduce these cells ex vivo. By targeting CD34, hematopoietic stem cells can in principle be transduced ex vivo without extensive purification. One of the primary advantages of lentiviral vectors is to allow direct in situ transduction of cells in vivo (16). In combination with the appropriate choice of targeting reagents, lentiviral vectors potentially provide a means for transduction of specific cells in vivo. One can envision a number of applications, including targeting of specific cells within tissues to correct metabolic defects and targeting of specific pathologic cells in infectious diseases or cancer. Future studies will further enhance the capabilities of this model system.
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ACKNOWLEDGMENTS |
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We thank Dong Sung An, Saskia Boisot, and Scott Kitchen for technical support, Takao Masuda for advice, and Liz Duarte and Rosie Taweesup for manuscript preparation. We thank Henry Huang and Akira Nakanishi for providing reagents.
This work was supported by NIH grants AI399975-01 and AI36555 and the Japanese Foundation for AIDS Prevention. S.K.-P.K. is a Research Fellow of the National Cancer Institute of Canada supported with funds provided by the Terry Fox Run.
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FOOTNOTES |
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* Corresponding author. Mailing address: UCLA AIDS Institute, 10833 Le Conte Ave., 11-934 Factor Bldg., Los Angeles, CA 90095. Phone: (310) 825-4793. Fax: (310) 794-7682. E-mail: rtaweesu{at}ucla.edu.
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Top
Abstract
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Materials and Methods
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Journal of Virology, September 2001, p. 8016-8020, Vol. 75, No. 17
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.17.8016-8020.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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