title: Gene therapy-based treatment for HIV-positive patients with malignancies.
abstract: Gene therapy for the treatment of HIV has long been a goal of many investigators. The majority of trials have involved the use of lymphocytes transduced with vectors promoting resistance to HIV infection or replication. Unfortunately, the results have been less than encouraging with low-level marking and, more importantly, clearance of these lymphocytes from the circulation. Conversely, gene-modified hematopoietic stem cells appear able to introduce foreign transgenes while avoiding immunologic clearance. Furthermore, the use of less toxic conditioning regimens for allogeneic transplantation provides an attractive approach to conferring HIV resistance while allowing treatment of HIV-related disorders such as malignancies. This combination of nonmyeloablative allogeneic transplantation using gene-modified hematopoietic stem cell theoretically overcomes the high transplant mortality associated with traditional conditioning regimens in patients with HIV as well as providing a self-renewing source of HIV-resistant cells. To assess the safety and feasibility of such an approach, a clinical protocol was initiated in those patients infected with HIV with a hematologic malignancy meeting the standard indications for allogeneic transplantation and provided here is an update to the previously published original report. Only patient 1 received genetically modified cells. Both patients tolerated the procedure with no effect on viral load and improved CD4 counts, and patient 1 remains in complete remission from acute myelogenous leukemia 3 years post transplant. Patient 2 also achieved clinical remission from chemorefractory Hodgkin's disease but died of relapsed disease 12 months after transplantation. Vector-transduced cells remain detectable at low levels more than 3 years post-transplantation, suggesting the potential for gene therapy as a reasonable goal for the treatment of HIV.
authors.affiliation: Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA. ElizabethK@intra.niddk.nih.gov
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kang
authors.forename: Moniek
authors.initials: M
authors.lastname: De Witte
authors.forename: Harry
authors.initials: H
authors.lastname: Malech
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Charles
authors.initials: C
authors.lastname: Carter
authors.forename: Susan F
authors.initials: SF
authors.lastname: Leitman
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
authors.forename: Richard
authors.initials: R
authors.lastname: Little
authors.forename: John F
authors.initials: JF
authors.lastname: Tisdale
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019070:Cell Lineage; D002986:Clinical Trials as Topic; D015694:Gene Products, rev / Q000235:genetics; D015750:Genes, gag / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015658:HIV Infections / Q000150:complications / Q000628:therapy*; D006689:Hodgkin Disease / Q000628:therapy; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009369:Neoplasms / Q000628:therapy* / Q000821:virology*; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D019076:Transgenes; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D054321:rev Gene Products, Human Immunodeficiency Virus
chemical_list: D015694:Gene Products, rev; D008562:Membrane Glycoproteins; D054321:rev Gene Products, Human Immunodeficiency Virus; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases