title: HIV-1 utilizes the CXCR4 chemokine receptor to infect multipotent hematopoietic stem and progenitor cells.
abstract: HIV infection is characterized by gradual immune system collapse and hematopoietic dysfunction. We recently showed that HIV enters multipotent hematopoietic progenitor cells and establishes both active cytotoxic and latent infections that can be reactivated by myeloid differentiation. However, whether these multipotent progenitors include long-lived hematopoietic stem cells (HSCs) that could establish viral reservoirs for the life of the infected person remains unknown. Here we provide direct evidence that HIV targets long-lived HSCs and show that infected HSCs yield stable, multilineage engraftment in a xenograft model. Furthermore, we establish that the capacity to use the chemokine receptor CXCR4 for entry determines whether a virus will enter multipotent versus differentiated progenitor cells. Because HSCs live for the life span of the infected person and are crucial for hematopoietic health, these data may explain the poor prognosis associated with CXCR4-tropic HIV infection and suggest HSCs as long-lived cellular reservoirs of latent HIV.
authors.affiliation: Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Carter
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: McNamara
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Adewunmi
authors.initials: A
authors.lastname: Onafuwa-Nuga
authors.affiliation: Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: James
authors.initials: J
authors.lastname: Riddell
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Bixby
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Savona
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, Center for Stem Cell Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
authors.affiliation: Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: klcollin@umich.edu.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Collins
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010455:Peptides / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D019562:Viral Load; D010948:Viral Plaque Assay; D056189:Viral Tropism; D017735:Virus Latency
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D006023:Glycoproteins; D010455:Peptides; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins