Improved safety of a replication-competent poxvirus-based HIV vaccine with the introduction of the HSV-TK/GCV suicide gene system.

INTRODUCTION: Replication-competent vaccinia viruses (VACVs) show prolonged antigen expression time and greater stimulation of immune responses than their replication-incompetent counterparts. However, there is the potential risk of serious post-vaccination complications, especially for children and immunocompromised individuals, leading to safety concerns about the reintroduction of VACV as a vaccine vector. In this study, we improved the safety of the vaccinia virus TianTan (VACV-TT) based HIV vaccine by introducing the HSV-TK/GCV suicide gene system, which is composed of the herpes simplex virus type 1 thymidine kinase gene (HSV-tk) and the antiviral drug ganciclovir (GCV).

MATERIALS AND METHODS: By inserting the HSV-tk gene into the replication-competent VACV-TT genome, a new vector, TT-TK (VACV-TT expressing the HSV-tk gene), and a candidate vaccine, TT-EnvTK (TT-TK expressing the HIV-1 env gene), were constructed.

RESULTS: The new vector TT-TK exhibited reduced replication capacity both in vitro and in vivo in the presence of GCV. GCV inhibited the replication of TT-TK in the brains of mice and skin of rabbits, and provided 100% protection in mice against lethal challenge with TT-TK at a dose of 80mg/kg/day. Furthermore, the candidate vaccine TT-EnvTK induced cellular and humoral immunity against HIV-1 antigen that was comparable to the immunity induced by VTKgpe (VACV-TT expressing HIV-1 env, gag, and pol genes).

DISCUSSION: These promising results suggest a new strategy to mitigate the potential risk of post-vaccination complications from replication-competent VACV-based HIV vaccines.