Granulocyte-macrophage colony-stimulating factor expressed by recombinant respiratory syncytial virus attenuates viral replication and increases the level of pulmonary antigen-presenting cells

Alexander Bukreyev, I. M. Belyakov, J. A. Berzofsky, B. R. Murphy, P. L. Collins

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

An obstacle to developing a vaccine against human respiratory syncytial virus (RSV) is that natural infection typically does not confer solid immunity to reinfection. To investigate methods to augment the immune response, recombinant RSV (rRSV) was constructed that expresses murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) from a transcription cassette inserted into the G-F intergenic region. Replication of rRSV/mGM-CSF in the upper and lower respiratory tracts of BALB/c mice was reduced 23- to 74- and 5- to 588-fold, respectively, compared to that of the parental rRSV. Despite this strong attenuation of replication, the level of RSV-specific serum antibodies induced by rRSV/mGM-CSF was comparable to, or marginally higher than, that of the parental rRSV. The induction of RSV-specific CD8+ cytotoxic T cells was moderately reduced during the initial infection, which might be a consequence of reduced antigen expression. Mice infected with rRSV/mGM-CSF had elevated levels of pulmonary mRNA for gamma interferon (IFN-γ) and interleukin 12 (IL-12) p40 compared to animals infected by wild-type rRSV. Elevated synthesis of IFN-γ could account for the restriction of RSV replication, as was observed previously with an IFN-γ-expressing rRSV. The accumulation of total pulmonary mononuclear cells and total CD4+ T lymphocytes was accelerated in animals infected with rRSV/mGM-CSF compared to that in animals infected with the control virus, and the level of IFN-γ-positive or IL-4-positive pulmonary CD4+ cells was elevated approximately twofold. The number of pulmonary lymphoid and myeloid dendritic cells and macrophages was increased up to fourfold in mice infected with rRSV/mGM-CSF compared to those infected with the parental rRSV, and the mean expression of major histocompatibility complex class II molecules, a marker of activation, was significantly increased in the two subsets of dendritic cells. Enhanced antigen presentation likely accounts for the maintenance of a strong antibody response despite reduced viral replication and would be a desirable property for a live attenuated rRSV vaccine.

Original languageEnglish (US)
Pages (from-to)12128-12140
Number of pages13
JournalJournal of Virology
Volume75
Issue number24
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

granulocyte-macrophage colony-stimulating factor
Respiratory Syncytial Viruses
antigen-presenting cells
Antigen-Presenting Cells
Granulocyte-Macrophage Colony-Stimulating Factor
virus replication
lungs
Lung
viruses
mice
Interferons
interferons
Dendritic Cells
Respiratory Syncytial Virus Vaccines
Human respiratory syncytial virus
dendritic cells
T-Lymphocytes
Attenuated Vaccines
Synthetic Vaccines
Intergenic DNA

ASJC Scopus subject areas

  • Immunology

Cite this

Granulocyte-macrophage colony-stimulating factor expressed by recombinant respiratory syncytial virus attenuates viral replication and increases the level of pulmonary antigen-presenting cells. / Bukreyev, Alexander; Belyakov, I. M.; Berzofsky, J. A.; Murphy, B. R.; Collins, P. L.

In: Journal of Virology, Vol. 75, No. 24, 2001, p. 12128-12140.

Research output: Contribution to journalArticle

@article{2d9d1ee353d141dd801808ea3b7ecde3,
title = "Granulocyte-macrophage colony-stimulating factor expressed by recombinant respiratory syncytial virus attenuates viral replication and increases the level of pulmonary antigen-presenting cells",
abstract = "An obstacle to developing a vaccine against human respiratory syncytial virus (RSV) is that natural infection typically does not confer solid immunity to reinfection. To investigate methods to augment the immune response, recombinant RSV (rRSV) was constructed that expresses murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) from a transcription cassette inserted into the G-F intergenic region. Replication of rRSV/mGM-CSF in the upper and lower respiratory tracts of BALB/c mice was reduced 23- to 74- and 5- to 588-fold, respectively, compared to that of the parental rRSV. Despite this strong attenuation of replication, the level of RSV-specific serum antibodies induced by rRSV/mGM-CSF was comparable to, or marginally higher than, that of the parental rRSV. The induction of RSV-specific CD8+ cytotoxic T cells was moderately reduced during the initial infection, which might be a consequence of reduced antigen expression. Mice infected with rRSV/mGM-CSF had elevated levels of pulmonary mRNA for gamma interferon (IFN-γ) and interleukin 12 (IL-12) p40 compared to animals infected by wild-type rRSV. Elevated synthesis of IFN-γ could account for the restriction of RSV replication, as was observed previously with an IFN-γ-expressing rRSV. The accumulation of total pulmonary mononuclear cells and total CD4+ T lymphocytes was accelerated in animals infected with rRSV/mGM-CSF compared to that in animals infected with the control virus, and the level of IFN-γ-positive or IL-4-positive pulmonary CD4+ cells was elevated approximately twofold. The number of pulmonary lymphoid and myeloid dendritic cells and macrophages was increased up to fourfold in mice infected with rRSV/mGM-CSF compared to those infected with the parental rRSV, and the mean expression of major histocompatibility complex class II molecules, a marker of activation, was significantly increased in the two subsets of dendritic cells. Enhanced antigen presentation likely accounts for the maintenance of a strong antibody response despite reduced viral replication and would be a desirable property for a live attenuated rRSV vaccine.",
author = "Alexander Bukreyev and Belyakov, {I. M.} and Berzofsky, {J. A.} and Murphy, {B. R.} and Collins, {P. L.}",
year = "2001",
doi = "10.1128/JVI.75.24.12128-12140.2001",
language = "English (US)",
volume = "75",
pages = "12128--12140",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "24",

}

TY - JOUR

T1 - Granulocyte-macrophage colony-stimulating factor expressed by recombinant respiratory syncytial virus attenuates viral replication and increases the level of pulmonary antigen-presenting cells

AU - Bukreyev, Alexander

AU - Belyakov, I. M.

AU - Berzofsky, J. A.

AU - Murphy, B. R.

AU - Collins, P. L.

PY - 2001

Y1 - 2001

N2 - An obstacle to developing a vaccine against human respiratory syncytial virus (RSV) is that natural infection typically does not confer solid immunity to reinfection. To investigate methods to augment the immune response, recombinant RSV (rRSV) was constructed that expresses murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) from a transcription cassette inserted into the G-F intergenic region. Replication of rRSV/mGM-CSF in the upper and lower respiratory tracts of BALB/c mice was reduced 23- to 74- and 5- to 588-fold, respectively, compared to that of the parental rRSV. Despite this strong attenuation of replication, the level of RSV-specific serum antibodies induced by rRSV/mGM-CSF was comparable to, or marginally higher than, that of the parental rRSV. The induction of RSV-specific CD8+ cytotoxic T cells was moderately reduced during the initial infection, which might be a consequence of reduced antigen expression. Mice infected with rRSV/mGM-CSF had elevated levels of pulmonary mRNA for gamma interferon (IFN-γ) and interleukin 12 (IL-12) p40 compared to animals infected by wild-type rRSV. Elevated synthesis of IFN-γ could account for the restriction of RSV replication, as was observed previously with an IFN-γ-expressing rRSV. The accumulation of total pulmonary mononuclear cells and total CD4+ T lymphocytes was accelerated in animals infected with rRSV/mGM-CSF compared to that in animals infected with the control virus, and the level of IFN-γ-positive or IL-4-positive pulmonary CD4+ cells was elevated approximately twofold. The number of pulmonary lymphoid and myeloid dendritic cells and macrophages was increased up to fourfold in mice infected with rRSV/mGM-CSF compared to those infected with the parental rRSV, and the mean expression of major histocompatibility complex class II molecules, a marker of activation, was significantly increased in the two subsets of dendritic cells. Enhanced antigen presentation likely accounts for the maintenance of a strong antibody response despite reduced viral replication and would be a desirable property for a live attenuated rRSV vaccine.

AB - An obstacle to developing a vaccine against human respiratory syncytial virus (RSV) is that natural infection typically does not confer solid immunity to reinfection. To investigate methods to augment the immune response, recombinant RSV (rRSV) was constructed that expresses murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) from a transcription cassette inserted into the G-F intergenic region. Replication of rRSV/mGM-CSF in the upper and lower respiratory tracts of BALB/c mice was reduced 23- to 74- and 5- to 588-fold, respectively, compared to that of the parental rRSV. Despite this strong attenuation of replication, the level of RSV-specific serum antibodies induced by rRSV/mGM-CSF was comparable to, or marginally higher than, that of the parental rRSV. The induction of RSV-specific CD8+ cytotoxic T cells was moderately reduced during the initial infection, which might be a consequence of reduced antigen expression. Mice infected with rRSV/mGM-CSF had elevated levels of pulmonary mRNA for gamma interferon (IFN-γ) and interleukin 12 (IL-12) p40 compared to animals infected by wild-type rRSV. Elevated synthesis of IFN-γ could account for the restriction of RSV replication, as was observed previously with an IFN-γ-expressing rRSV. The accumulation of total pulmonary mononuclear cells and total CD4+ T lymphocytes was accelerated in animals infected with rRSV/mGM-CSF compared to that in animals infected with the control virus, and the level of IFN-γ-positive or IL-4-positive pulmonary CD4+ cells was elevated approximately twofold. The number of pulmonary lymphoid and myeloid dendritic cells and macrophages was increased up to fourfold in mice infected with rRSV/mGM-CSF compared to those infected with the parental rRSV, and the mean expression of major histocompatibility complex class II molecules, a marker of activation, was significantly increased in the two subsets of dendritic cells. Enhanced antigen presentation likely accounts for the maintenance of a strong antibody response despite reduced viral replication and would be a desirable property for a live attenuated rRSV vaccine.

UR - http://www.scopus.com/inward/record.url?scp=0035198506&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035198506&partnerID=8YFLogxK

U2 - 10.1128/JVI.75.24.12128-12140.2001

DO - 10.1128/JVI.75.24.12128-12140.2001

M3 - Article

VL - 75

SP - 12128

EP - 12140

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 24

ER -