Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization

Alex K. Lam; Romin Roshan; Wendell Miley; Nazzarena Labo; James Zhen; Andrew P. Kurland; Celine Cheng; Haigen Huang; Pu Lin Teng; Claire Harelson; Danyang Gong; Ying K. Tam; Caius G. Radu; Marta Epeldegui; Jeffrey R. Johnson; Z. Hong Zhou; Denise Whitby; Ting Ting Wu

doi:10.1128/jvi.01600-22

Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization

Alex K. Lam, Romin Roshan, Wendell Miley, Nazzarena Labo, James Zhen, Andrew P. Kurland, Celine Cheng, Haigen Huang, Pu Lin Teng, Claire Harelson, Danyang Gong, Ying K. Tam, Caius G. Radu, Marta Epeldegui, Jeffrey R. Johnson, Z. Hong Zhou, Denise Whitby, Ting Ting Wu

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development.

Original language	English
Journal	Journal of Virology
Volume	97
Issue number	2
DOIs	https://doi.org/10.1128/jvi.01600-22
State	Published - Feb 2023

Keywords

KSHV
antibody function
complement
neutralizing antibodies
vaccine

Access to Document

10.1128/jvi.01600-22

Cite this

Lam, A. K., Roshan, R., Miley, W., Labo, N., Zhen, J., Kurland, A. P., Cheng, C., Huang, H., Teng, P. L., Harelson, C., Gong, D., Tam, Y. K., Radu, C. G., Epeldegui, M., Johnson, J. R., Zhou, Z. H., Whitby, D., & Wu, T. T. (2023). Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization. Journal of Virology, 97(2). https://doi.org/10.1128/jvi.01600-22

@article{eac9c5b8b2f147d384405a3e812bbb82,

title = "Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization",

abstract = "Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development.",

keywords = "KSHV, antibody function, complement, neutralizing antibodies, vaccine",

author = "Lam, {Alex K.} and Romin Roshan and Wendell Miley and Nazzarena Labo and James Zhen and Kurland, {Andrew P.} and Celine Cheng and Haigen Huang and Teng, {Pu Lin} and Claire Harelson and Danyang Gong and Tam, {Ying K.} and Radu, {Caius G.} and Marta Epeldegui and Johnson, {Jeffrey R.} and Zhou, {Z. Hong} and Denise Whitby and Wu, {Ting Ting}",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 Lam et al.",

year = "2023",

month = feb,

doi = "10.1128/jvi.01600-22",

language = "English",

volume = "97",

journal = "Journal of Virology",

issn = "0022-538X",

publisher = "American Society for Microbiology",

number = "2",

}

Lam, AK, Roshan, R, Miley, W, Labo, N, Zhen, J, Kurland, AP, Cheng, C, Huang, H, Teng, PL, Harelson, C, Gong, D, Tam, YK, Radu, CG, Epeldegui, M, Johnson, JR, Zhou, ZH, Whitby, D & Wu, TT 2023, 'Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization', Journal of Virology, vol. 97, no. 2. https://doi.org/10.1128/jvi.01600-22

TY - JOUR

T1 - Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization

AU - Lam, Alex K.

AU - Roshan, Romin

AU - Miley, Wendell

AU - Labo, Nazzarena

AU - Zhen, James

AU - Kurland, Andrew P.

AU - Cheng, Celine

AU - Huang, Haigen

AU - Teng, Pu Lin

AU - Harelson, Claire

AU - Gong, Danyang

AU - Tam, Ying K.

AU - Radu, Caius G.

AU - Epeldegui, Marta

AU - Johnson, Jeffrey R.

AU - Zhou, Z. Hong

AU - Whitby, Denise

AU - Wu, Ting Ting

PY - 2023/2

Y1 - 2023/2

N2 - Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development.

AB - Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development.

KW - KSHV

KW - antibody function

KW - complement

KW - neutralizing antibodies

KW - vaccine

UR - http://www.scopus.com/inward/record.url?scp=85149154747&partnerID=8YFLogxK

U2 - 10.1128/jvi.01600-22

DO - 10.1128/jvi.01600-22

M3 - Article

C2 - 36757205

AN - SCOPUS:85149154747

SN - 0022-538X

VL - 97

JO - Journal of Virology

JF - Journal of Virology

IS - 2

ER -

Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization

Abstract

Keywords

Access to Document

Fingerprint

Cite this