Construction of a minimal HIV-1 variant that selectively replicates in leukemic derived T-cell lines: towards a new virotherapy approach.
T-cell acute lymphoblastic leukemia is a high-risk type of blood-cell cancer. We analyzed the possibility of developing virotherapy for T-cell acute lymphoblastic leukemia. Virotherapy is based on the exclusive replication of a virus in leukemic cells, leading to the selective removal of these malignant cells. We constructed a minimized derivative of HIV-1, a complex lentivirus encoding multiple accessory functions that are essential for virus replication in untransformed cells, but dispensable in leukemic T cells. This mini-HIV virus has five deletions (vif, vpR, vpU, nef, and U3) and replicated in the SupT1 cell line, but did not replicate in normal peripheral blood mononuclear cells. The stripped down mini-HIV variant was also able to efficiently remove leukemic cells from a mixed culture with untransformed control cells. In contrast to wild-type HIV-1, we did not observe bystander killing in mixed culture experiments with the mini-HIV variant. Furthermore, viral escape was not detected in long-term cultures. The mini-HIV variant that uses CD4 and CXCR4 for cell entry could potentially be used against CXCR4-expressing malignancies such as T-lymphoblastic leukemia/lymphoma, natural killer leukemia, and some myeloid leukemias.
Jeeninga
Rienk E
RE
Department of Human Retrovirology, Emma Children Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Jan
Barbara
B
van der Linden
Birgit
B
van den Berg
Henk
H
Berkhout
Ben
B
D015704:CD4 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D005260:Female; D017353:Gene Deletion; D015754:Genes, nef / Q000235:genetics; D016341:Genes, vif / Q000235:genetics; D016334:Genes, vpr / Q000235:genetics; D016338:Genes, vpu / Q000235:genetics; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000821:virology*; D014779:Virus Replication
D015704:CD4 Antigens; D019718:Receptors, CXCR4