Vectored antibody gene delivery restores host B and T cell control of persistent viral infection

Yusuf I Ertuna; Benedict Fallet; Anna-Friederike Marx; Mirela Dimitrova; Anna Lena Kastner; Ingrid Wagner; Doron Merkler; Daniel D Pinschewer

doi:10.1016/j.celrep.2021.110061

Vectored antibody gene delivery restores host B and T cell control of persistent viral infection

Cell Rep. 2021 Nov 30;37(9):110061. doi: 10.1016/j.celrep.2021.110061.

Authors

Yusuf I Ertuna¹, Benedict Fallet¹, Anna-Friederike Marx¹, Mirela Dimitrova¹, Anna Lena Kastner¹, Ingrid Wagner², Doron Merkler³, Daniel D Pinschewer⁴

Affiliations

¹ University of Basel, Department of Biomedicine-Haus Petersplatz, Division of Experimental Virology, 4009 Basel, Switzerland.
² Department of Pathology and Immunology, Geneva Faculty of Medicine, Geneva University Hospital, 1211 Geneva, Switzerland.
³ Department of Pathology and Immunology, Geneva Faculty of Medicine, Geneva University Hospital, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland.
⁴ University of Basel, Department of Biomedicine-Haus Petersplatz, Division of Experimental Virology, 4009 Basel, Switzerland. Electronic address: daniel.pinschewer@unibas.ch.

PMID: 34852228
DOI: 10.1016/j.celrep.2021.110061

Abstract

Passive antibody therapy and vectored antibody gene delivery (VAGD) in particular offer an innovative approach to combat persistent viral diseases. Here, we exploit a small animal model to investigate synergies of VAGD with the host's endogenous immune defense for treating chronic viral infection. An adeno-associated virus (AAV) vector delivering the lymphocytic choriomeningitis virus (LCMV)-neutralizing antibody KL25 (AAV-KL25) establishes protective antibody titers for >200 days. When therapeutically administered to chronically infected immunocompetent wild-type mice, AAV-KL25 affords sustained viral load control. In contrast, viral mutational escape thwarts therapeutic AAV-KL25 effects when mice are unable to mount LCMV-specific antibody responses or lack CD8⁺ T cells. VAGD augments antiviral germinal center B cell and antibody-secreting cell responses and reduces inhibitory receptor expression on antiviral CD8⁺ T cells. These results indicate that VAGD fortifies host immune defense and synergizes with B cell and CD8 T cell responses to restore immune control of chronic viral infection.

Keywords: CD8 T cell response; Functional Cure; T cell exhaustion; antiviral antibody response; germinal center B cell response; inhibitory receptor; lymphocytic choriomeningitis virus; persistent viral infection; vectored antibody gene delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / pharmacology*
Antibodies, Viral / pharmacology*
B-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / immunology*
Genes, Immunoglobulin*
Germinal Center
Lymphocytic Choriomeningitis / drug therapy
Lymphocytic Choriomeningitis / immunology*
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / immunology*
Mice
Mice, Inbred C57BL
Viral Load

Substances

Antibodies, Neutralizing
Antibodies, Viral