title: Multilineage polyclonal engraftment of Cal-1 gene-modified cells and in vivo selection after SHIV infection in a nonhuman primate model of AIDS.
abstract: We have focused on gene therapy approaches to induce functional cure/remission of HIV-1 infection. Here, we evaluated the safety and efficacy of the clinical grade anti-HIV lentiviral vector, Cal-1, in pigtailed macaques (Macaca nemestrina). Cal-1 animals exhibit robust levels of gene marking in myeloid and lymphoid lineages without measurable adverse events, suggesting that Cal-1 transduction and autologous transplantation of hematopoietic stem cells are safe, and lead to long-term, multilineage engraftment following myeloablative conditioning. Ex vivo, CD4+ cells from transplanted animals undergo positive selection in the presence of simian/human immunodeficiency virus (SHIV). In vivo, Cal-1 gene-marked cells are evident in the peripheral blood and in HIV-relevant tissue sites such as the gastrointestinal tract. Positive selection for gene-marked cells is observed in blood and tissues following SHIV challenge, leading to maintenance of peripheral blood CD4+ T-cell counts in a normal range. Analysis of Cal-1 lentivirus integration sites confirms polyclonal engraftment of gene-marked cells. Following infection, a polyclonal, SHIV-resistant clonal repertoire is established. These findings offer strong preclinical evidence for safety and efficacy of Cal-1, present a new method for tracking protected cells over the course of virus-mediated selective pressure in vivo, and reveal previously unobserved dynamics of virus-dependent T-cell selection.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Peterson
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Haworth
authors.affiliation: Calimmune, Inc. , Los Angeles, California, USA.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Burke
authors.affiliation: Washington National Primate Research Center , Seattle, Washington, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Polacino
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Krystin K
authors.initials: KK
authors.lastname: Norman
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Adair
authors.affiliation: Washington National Primate Research Center, Seattle, Washington, USA; Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
authors.forename: Shiu-Lok
authors.initials: SL
authors.lastname: Hu
authors.affiliation: Calimmune, Inc. , Los Angeles, California, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bartlett
authors.affiliation: Calimmune, Inc. , Los Angeles, California, USA.
authors.forename: Geoff P
authors.initials: GP
authors.lastname: Symonds
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem