Conditional reduction of human immunodeficiency virus type 1 replication by a gain-of-herpes simplex virus 1 thymidine kinase function.
The development of an effective vaccine for human immunodeficiency virus type 1 (HIV-1) would be a major advance toward controlling the AIDS pandemic. Several disparate strategies for a safe and effective HIV vaccine have been proposed. Recent data suggest that loss-of-function live-attenuated virus could be a safe lentivirus vaccine. Here, we propose a gain-of-function approach that can complement loss-of-function in enhancing the safety profile of a live-attenuated virus. We describe an example in which ganciclovir (GCV) was used to treat effectively nef(-)HIV-1 engineered to express herpes simplex virus (HSV-1) thymidine kinase (TK). This treatment was found to be highly efficient in controlling HIV-1 spread in tissue culture and in a small animal (hu-PBL-SCID) model. We demonstrate that one distinct advantage of GCV-HSV-TK treatment is the elimination of integrated proviruses, a goal not easily achieved with other antiretrovirals.
Smith
S M
SM
Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0460, USA.
Markham
R B
RB
Jeang
K T
KT
D016915:AIDS Vaccines; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D015774:Ganciclovir / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D007739:L Cells; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000276:immunology / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000378:metabolism*; D014613:Vaccines, Attenuated; D014779:Virus Replication / Q000187:drug effects*
D016915:AIDS Vaccines; D000998:Antiviral Agents; D014613:Vaccines, Attenuated; D013937:Thymidine Kinase; D015774:Ganciclovir