title: Improved safety of a replication-competent poxvirus-based HIV vaccine with the introduction of the HSV-TK/GCV suicide gene system.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  These promising results suggest a new strategy to mitigate the potential risk of post-vaccination complications from replication-competent VACV-based HIV vaccines.
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China; Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China; Key Laboratory of Molecular Microbiology and Biotechnology (Ministry of Education) and Key Laboratory of Microbial Functional Genomics (Tianjin), College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Qicheng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Hou
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China. Electronic address: yingliucdc@gmail.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China; School of Medicine, Nankai University, Tianjin, China. Electronic address: yshao08@gmail.com.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology*; D041722:Genes, Transgenic, Suicide; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D000071497:Immunogenicity, Vaccine; D051379:Mice; D008807:Mice, Inbred BALB C; D011817:Rabbits; D013937:Thymidine Kinase / Q000235:genetics; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D016915:AIDS Vaccines; D014614:Vaccines, Synthetic; D013937:Thymidine Kinase; D015774:Ganciclovir
keywords: HIV vaccine; HSV-1 thymidine kinase/ganciclovir; Replication-competent viral vector; Suicide gene system; Vaccinia virus TianTan