title: Human immunodeficiency virus inhibits multilineage hematopoiesis in vivo.
abstract: Human immunodeficiency virus type 1 (HIV-1)-infected individuals often exhibit multiple hematopoietic abnormalities reaching far beyond loss of CD4(+) lymphocytes. We used the SCID-hu (Thy/Liv) mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues), which provides an in vivo system whereby human pluripotent hematopoietic progenitor cells can be maintained and undergo T-lymphoid differentiation and wherein HIV-1 infection causes severe depletion of CD4-bearing human thymocytes. Herein we show that HIV-1 infection rapidly and severely decreases the ex vivo recovery of human progenitor cells capable of differentiation into both erythroid and myeloid lineages. However, the total CD34+ cell population is not depleted. Combination antiretroviral therapy administered well after loss of multilineage progenitor activity reverses this inhibitory effect, establishing a causal role of viral replication. Taken together, our results suggest that pluripotent stem cells are not killed by HIV-1; rather, a later stage important in both myeloid and erythroid differentiation is affected. In addition, a primary virus isolated from a patient exhibiting multiple hematopoietic abnormalities preferentially depleted myeloid and erythroid colony-forming activity rather than CD4-bearing thymocytes in this system. Thus, HIV-1 infection perturbs multiple hematopoietic lineages in vivo, which may explain the many hematopoietic defects found in infected patients.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Koka
authors.forename: J K
authors.initials: JK
authors.lastname: Fraser
authors.forename: Y
authors.initials: Y
authors.lastname: Bryson
authors.forename: G C
authors.initials: GC
authors.lastname: Bristol
authors.forename: G M
authors.initials: GM
authors.lastname: Aldrovandi
authors.forename: E S
authors.initials: ES
authors.lastname: Daar
authors.forename: J A
authors.initials: JA
authors.lastname: Zack
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D015658:HIV Infections / Q000097:blood* / Q000503:physiopathology*; D015497:HIV-1 / Q000502:physiology*; D006410:Hematopoiesis; D006801:Humans; D007223:Infant; D051379:Mice; D016513:Mice, SCID