Expression of a Tat-inducible herpes simplex virus-thymidine kinase gene protects acyclovir-treated CD4 cells from HIV-1 spread by conditional suicide and inhibition of reverse transcription.
Cellular expression of the herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene promotes cell death in the presence of specific nucleoside analog substrates such as acyclovir (ACV). We have reported that lymphoid CD4+ cells harboring an HSV1-TK gene, under the transcriptional control of the HIV-1 long terminal repeat (HUT-TK), are completely protected from HIV-1 spread in the presence of 10 microM ACV. In this report we clarify the efficiency, generality, and mechanism of this protective effect. We show that the protection from HIV-1 spread in HUT-TK cells obtains from both an inhibition of HIV reverse transcription by ACV metabolites and an HIV-induced and ACV-dependent cell killing. We also demonstrate that monocytic cells harboring the HIV-1-inducible HSV1-TK gene are protected from HIV spread in the presence of ACV. These observations facilitate the design of therapeutic strategies to limit HIV replication based on HSV1-TK expression.
Caruso
M
M
Laboratoire de Biologie et Génétique des Pathologies Immunitaires, CNRS URA D1463, Hôpital de la Pitié-Salpétrière, Paris, France.
Salomon
B
B
Zhang
S
S
Brisson
E
E
Clavel
F
F
Lowy
I
I
Klatzmann
D
D
D000212:Acyclovir / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D015696:Gene Products, tat / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D013937:Thymidine Kinase; D000212:Acyclovir