title: Positive selection of mC46-expressing CD4+ T cells and maintenance of virus specific immunity in a primate AIDS model.
abstract: Despite continued progress in the development of novel antiretroviral therapies, it has become increasingly evident that drug-based treatments will not lead to a functional or sterilizing cure for HIV(+) patients. In 2009, an HIV(+) patient was effectively cured of HIV following allogeneic transplantation of hematopoietic stem cells (HSCs) from a CCR5(-/-) donor. The utility of this approach, however, is severely limited because of the difficulty in finding matched donors. Hence, we studied the potential of HIV-resistant stem cells in the autologous setting in a nonhuman primate AIDS model and incorporated a fusion inhibitor (mC46) as the means for developing infection-resistant cells. Pigtail macaques underwent identical transplants and Simian-Human Immunodeficiency Virus (SHIV) challenge procedures with the only variation between control and mC46 macaques being the inclusion of a fusion-inhibitor expression cassette. Following SHIV challenge, mC46 macaques, but not control macaques, showed a positive selection of gene-modified CD4(+) T cells in peripheral blood, gastrointestinal tract, and lymph nodes, accounting for >90% of the total CD4(+) T-cell population. mC46 macaques also maintained high frequencies of SHIV-specific, gene-modified CD4(+) T cells, an increase in nonmodified CD4(+) T cells, enhanced cytotoxic T lymphocyte function, and antibody responses. These data suggest that HSC protection may be a potential alternative to conventional antiretroviral therapy in patients with HIV/AIDS.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Younan
authors.forename: Patricia
authors.initials: P
authors.lastname: Polacino
authors.forename: John P
authors.initials: JP
authors.lastname: Kowalski
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Peterson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maurice
authors.forename: Nathaniel P
authors.initials: NP
authors.lastname: Williams
authors.forename: On
authors.initials: O
authors.lastname: Ho
authors.forename: Grant D
authors.initials: GD
authors.lastname: Trobridge
authors.forename: Dorothee
authors.initials: D
authors.lastname: Von Laer
authors.forename: Martin
authors.initials: M
authors.lastname: Prlic
authors.forename: Brian C
authors.initials: BC
authors.lastname: Beard
authors.forename: Stephen
authors.initials: S
authors.lastname: DeRosa
authors.forename: Shiu-Lok
authors.initials: SL
authors.lastname: Hu
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D064987:Cell- and Tissue-Based Therapy; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008254:Macaca nemestrina; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000276:immunology* / Q000628:therapy / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D019562:Viral Load; D014766:Viremia / Q000276:immunology / Q000821:virology
chemical_list: D000956:Antigens, Viral; C515020:C46 HIV-1 fusion inhibitory peptide; D011993:Recombinant Fusion Proteins