Therapeutic effect of a gag-nuclease fusion protein against retroviral infection in vivo

Recently, remarkable progress has been made in developing effective combina tion drug therapies that can control but not cure retroviral replication. E ven when effective, these drug regimens are toxic, they require demanding a dministration schedules, and resistant viruses can emerge. Thus the need fo r new gene-based therapies continues. In one such approach, capsid-targeted viral inactivation (CTVI), nucleases fused to viral coat proteins are expr essed in infected cells and become incorporated during virion assembly. CTV I can eliminate infectious murine retrovirus titer in tissue culture, Here we describe transgenic mice expressing fusions of the Moloney murine leukem ia virus (Mo-MuLV) Gag protein to staphylococcal nuclease, This work tests the protective effect and demonstrates in vivo proof-of-principle of CTVI i n transgenic mice expressing endogenous proviral copies of Mo-MuLV, The ant iviral protein-expressing mice are phenotypically normal, attesting to the lack of toxicity of the fusion protein. The Mo-MuLV infection was much less virulent in transgenic littermates than in nontransgenic littermates, Gag- nuclease expression reduced infectious titers in blood up to 10-fold, decre ased splenomegaly and leukemic infiltration, and increased life spans up to 2.5-fold in transgenic relative to nontransgenic infected animals. These r esults suggest that gene therapies based on similar fusion proteins, design ed to attack human immunodeficiency virus or other retroviruses, could prov ide substantial therapeutic benefits.