acyclovir and Leukemia--T-Cell

Serious ocular disease following varicella (chickenpox) is rare in children. In addition, retinitis in children with hematologic malignancies may present a difficult diagnostic challenge because infectious retinitis may mimic leukemic involvement of the eye. We report a 7-year-old patient with T-cell acute lymphoblastic leukemia in remission who presented with visual complaints 2 weeks after developing chickenpox. Ophthalmologic evaluation revealed acute retinitis in the right eye. Prolonged therapy with acyclovir resulted in near complete recovery. Early diagnosis of VZV retinopathy and aggressive antiviral treatment is critical to prevent acute and long-term ocular sequelae.

Topics: Acyclovir; Antiviral Agents; Chickenpox; Chickenpox Vaccine; Child; Diagnosis, Differential; Humans; Leukemia, T-Cell; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retinitis

Retroviral transfer of Herpes simplex virus thymidine kinase to T cells has been used to confer sensitivity to the antiviral agent ganciclovir. This has allowed therapeutic approaches to be developed in which T cells mediating graft-versus-host disease after bone marrow transplantation can be selectively eliminated by the administration of ganciclovir. Although the strategy has been shown to be generally successful in early clinical trials, there are concerns about possible resistance to ganciclovir and the risk of myelosuppressive side-effects at the doses required to induce T cell suicide. We have incorporated the enhanced mutant HSV-TKSR39 into retroviral vectors tailored to exhibit high levels of expression in T cells and have used protocols optimized for the transduction and selection of primary lymphocytes. We demonstrate that leukemic and primary T cells can be efficiently transduced and highly enriched under conditions that should be readily adaptable for clinical use. T cells carrying HSV-TKSR39 were inhibited by exposure to ganciclovir at concentrations an order of magnitude below those required for wild-type HSV-TK. The less toxic agent aciclovir also eliminated T cells transduced with HSV-TKSR39 (but not HSV-TK), underlining the increased therapeutic potential of the mutant suicide gene system in the bone marrow transplantation setting.

Topics: Acyclovir; Antiviral Agents; Bone Marrow Transplantation; Cell Line; Cells, Cultured; Ganciclovir; Genetic Therapy; Genetic Vectors; Graft vs Host Disease; Humans; Leukemia, T-Cell; Mutation; Retroviridae; Simplexvirus; T-Lymphocytes; Thymidine Kinase; Transduction, Genetic

Herpesvirus saimiri can be used as an efficient gene expression vector for human T lymphocytes and thus may allow applications in experimental leukemia therapy. We constructed recombinant viruses for the functional expression of the thymidine kinase (TK) of herpes simplex virus type 1 (HSV) as a suicide gene. These viruses reliably allowed the targeted elimination of transduced nonpermissive human T cells in vitro after the administration of ganciclovir. To test the reliability of this function under the most stringent permissive conditions, in this study we analyzed the influence of the prodrugs ganciclovir and acyclovir in common marmosets on the acute leukemogenesis induced by either wild-type herpesvirus saimiri C488 or by a recombinant derivative expressing TK of HSV. Antiviral drug treatment did not influence the rapid development of acute disease. In contrast, the presence of the HSV tk gene resulted in a faster disease progression. In addition, HSV TK-expressing viruses showed faster replication than wild-type virus in culture at low serum concentrations. Thus, HSV TK accelerates the replication of herpesvirus saimiri and enhances its pathogenicity. This should be generally considered when HSV TK is applied as a transgene in replication-competent DNA virus vectors for gene therapy.

Topics: Acyclovir; Animals; Callithrix; Cell Line; Cells, Cultured; Ganciclovir; Genetic Vectors; Herpes Simplex; Humans; Leukemia, T-Cell; Simplexvirus; T-Lymphocytes; Thymidine Kinase; Virulence

Adult T-cell leukemia (ATL), a disorder associated with high mortality rates, arises from human T-lymphotropic virus type I (HTLV-I)-infected CD4+ T cells. We designed a retroviral vector-based gene therapy approach to ATL. The long terminal repeat (LTR) of HTLV-I is transactivated by the viral tax protein. We constructed a hybrid gene consisting of herpes simplex virus thymidine kinase (HSV TK) under the control of the HTLV-I LTR and inserted it into a retroviral vector. When HTLV-I-transformed and tax-expressing human T-cell lines were infected with this recombinant retrovirus (LNLTK alpha virus), they expressed high levels of HSV TK and exhibited increased sensitivity to acyclovir, a nucleoside analog that is converted to the toxic anabolite after phosphorylation by the HSV TK. On the other hand, the retroviral infection had little effect on acyclovir-induced cytotoxicity in HTLV-I-negative human hematopoietic cell lines. Our data may provide the prospect of the gene therapy for ATL by tax-targeted selective elimination of leukemic cells.

Topics: Acyclovir; Blotting, Southern; CD4-Positive T-Lymphocytes; Cell Death; Cell Line, Transformed; DNA, Recombinant; Gene Expression; Gene Products, tax; Gene Transfer Techniques; Genetic Therapy; Hematopoietic Stem Cells; Human T-lymphotropic virus 1; Humans; Leukemia, T-Cell; Repetitive Sequences, Nucleic Acid; Retroviridae; Simplexvirus; Thymidine Kinase

Topics: Acyclovir; B-Lymphocytes; Drug Therapy, Combination; Female; Fluorescein Angiography; Herpes Zoster; Humans; Leukemia, T-Cell; Lymphoma; Middle Aged; Necrosis; Recurrence; Retinitis; Vidarabine