title: Development of hematopoietic stem cell based gene therapy for HIV-1 infection: considerations for proof of concept studies and translation to standard medical practice.
abstract: Over the past 15 years we have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). We propose that the expression of selected RNA-based HIV-1 inhibitors in the CD4+ cells derived from GM-HSPC will protect them from HIV-1 infection and results in a sufficient immune repertoire to control HIV-1 viremia resulting in a functional cure for HIV-1/AIDS. Additionally, it is possible that the subset of protected T cells will also be able to facilitate the immune-based elimination of latently infected cells if they can be activated to express viral antigens. Thus, a single dose of disease resistant GM-HSPC could provide an effective treatment for HIV-1+ patients who require (or desire) an alternative to lifelong antiretroviral chemotherapy. We describe herein the results from several pilot clinical studies in HIV-1 patients and our strategies to develop second generation vectors and clinical strategies for HIV-1+ patients with malignancy who require ablative chemotherapy as part of treatment and others without malignancy. The important issues related to stem cell source, patient selection, conditioning regimen and post-infusion correlative studies become increasingly complex and are discussed herein.
authors.affiliation: Department of Virology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA. ddigiusto@coh.org.
authors.forename: David L
authors.initials: DL
authors.lastname: DiGiusto
authors.forename: Rodica
authors.initials: R
authors.lastname: Stan
authors.forename: Amrita
authors.initials: A
authors.lastname: Krishnan
authors.forename: Haitang
authors.initials: H
authors.lastname: Li
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
authors.forename: John A
authors.initials: JA
authors.lastname: Zaia
mesh_terms: D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation / Q000821:virology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D015316:Genetic Therapy; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000628:therapy* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D057170:Translational Research, Biomedical; D055815:Young Adult