Selective killing of CD4+ cells harboring a human immunodeficiency virus-inducible suicide gene prevents viral spread in an infected cell population.
We have stably expressed in CD4+ lymphoid cells the herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene under the control of the human immunodeficiency virus (HIV) promoter and transactivation response element sequences. Upon HIV infection these regulatory sequences were transactivated, switching on high-level expression of HSV1-TK. This in turn caused the death of HIV-infected cells when they were cultured in the presence of acyclovir, a nucleoside analog that becomes toxic after phosphorylation by HSV1-TK. The elimination of HIV-infected cells resulted in the arrest of HIV spreading in the culture. Complete protection of HSV1-TK-expressing cells was obtained using acyclovir concentrations that are commonly detected in the plasma of patients treated for HSV1 infection. Thus, expression of this DNA construct generates a pool of CD4+ booby-trapped cells that, as a population, are resistant to HIV infection. Our data provide a rationale for the use of suicide genes in the design of gene therapy of HIV infection.
Laboratoire de Biologie et Génétique des Pathologies Immunitaires, Hôpital de la Pitié-Salpêtrière, Paris, France.
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M
Caruso
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Klatzmann
D000212:Acyclovir / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004274:DNA, Recombinant; D015870:Gene Expression; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics* / Q000254:growth & development*; D006801:Humans; D066298:In Vitro Techniques; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects
D004274:DNA, Recombinant; D013937:Thymidine Kinase; D000212:Acyclovir