Selective induction of toxicity to human cells expressing human immunodeficiency virus type 1 Tat by a conditionally cytotoxic adenovirus vector.
The human immunodeficiency viruses (HIVs) primarily infect CD4+ T lymphocytes, leading eventually to the development of a systemic immune dysfunction termed acquired immunodeficiency syndrome (AIDS). An attractive strategy to combat HIV-mediated pathogenesis would be to eliminate the initial pool of infected cells and thus prevent disease progression. We have engineered a replication-defective, conditionally cytotoxic adenovirus vector, Ad-tk, whose action is dependent on the targeted expression of the herpes simplex virus type 1 thymidine kinase gene (tk), cloned downstream of the HIV-1 long terminal repeat, in human cells expressing the HIV-1 transcriptional activator Tat. Infection of Tat-expressing human HeLa or Jurkat cells with Ad-tk resulted in high-level tk expression, which was not deleterious to the viability of these cells. However, in the presence of the antiherpetic nucleoside analog ganciclovir, Ad-tk infection resulted in a massive reduction in the viability of these Tat-expressing cell lines. As adenoviruses are natural passengers of the human lymphoid system, our results suggest adenovirus vector-based strategies for the targeted expression, under the control of cis-responsive HIV regulatory elements, of cytotoxic agents in HIV-infected cells for the therapy of HIV-mediated pathogenesis.
Venkatesh
L K
LK
Institute for Molecular Virology, Saint Louis University Medical Center, MO 63110.
Arens
M Q
MQ
Subramanian
T
T
Chinnadurai
G
G
D000260:Adenoviruses, Human / Q000235:genetics; D002470:Cell Survival; D003001:Cloning, Molecular; D015870:Gene Expression; D015694:Gene Products, rev / Q000235:genetics; D015696:Gene Products, tat / Q000235:genetics*; D005822:Genetic Vectors; D015658:HIV Infections / Q000628:therapy*; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D066298:In Vitro Techniques; D012333:RNA, Messenger / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus
D015694:Gene Products, rev; D015696:Gene Products, tat; D012333:RNA, Messenger; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; D013937:Thymidine Kinase