HIV-1-induced thymocyte depletion is associated with indirect cytopathicity and infection of progenitor cells in vivo

Su, Lishan; Kaneshima, Hideto; Bonyhadi, Mark; Salimi, Suzan; Kraft, Daniel; Rabin, Linda; McCune, Joseph M.

doi:10.1016/1074-7613(95)90076-4

Cited by 204 publications

(222 citation statements)

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“…11 Human leukocytes (CD45 ϩ ) were analyzed for CD3, CD4, CD8, CD45RO, CD19, CCR5(2D7), and CXCR4(12G5) by fluorescenceactivated cell sorting (FACS). 13 …”

Section: Methodsmentioning

confidence: 99%

“…Central and peripheral lymphoid organs were harvested to investigate HIV replication and pathogenesis in the thymus, spleen, and lymph nodes. [13][14][15][16] To detect infectious HIV-1 in lymphoid organs, splenocytes or thymocytes were cocultured with PHA-activated peripheral blood mononuclear cells (PBMCs) for 14 days. 13,17 …”

Section: Hiv-1 Infection and Pathogenesis In Dko-hu Hsc Micementioning

confidence: 99%

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HIV-1 infection and pathogenesis in a novel humanized mouse model

Zhang

Kovalev

2006

Blood

127

136

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IntroductionThe hallmarks of AIDS are high levels of HIV-1 infection, depletion of CD4 ϩ T cells, and loss of immunity. The mechanism of HIV-1 immunopathogenesis is not clear because human patients are the only hosts that support high levels of HIV-1 replication and develop AIDS. Extensive studies have been performed in primate models with either low levels of HIV-1 replication (HIV-1 in chimps) or a different virus (simian immunodeficiency virus [SIV] or simian/human immunodeficiency virus [SHIV] in monkeys). 1-3 HIV-1 fails to infect murine cells due to blocks at multiple steps of the HIV life cycle. The mouse with a reconstituted human immune system would be an ideal small animal model for studying HIV-1 infection and pathogenesis. A number of human-mouse chimeric models have been developed, but with only limited success. The severe combined immunodeficient (SCID)-hu Thy/Liv mouse has an intact human thymus organ, thus allowing investigation of HIV-1 pathogenesis in a human lymphoid organ. [4][5][6] However, very low levels of human T cells are detected in the peripheral lymphoid organs or blood. The hu-peripheral blood lymphocyte (PBL)-SCID mouse supports transient and selective engraftment of xenoreactive human T cells. 7,8 Human CD34 ϩ cells transplanted into SCID or nonobese diabetic (NOD)/SCID mice lead to generation of mainly human myeloid and B cells in the mouse bone marrow, but inefficient generation of human T cells. 9,10 When CD34 ϩ human hematopoietic stem cells (HSCs)/hematopoietic stem progenitor cells (HSPCs) are injected directly into the liver of newborn Rag2-␥C double-knockout (DKO) mice, which lack T, B, and natural killer (NK) cells, the newborn liver environment of DKO mice supports efficient engraftment and development of a functional human immune system in central and peripheral lymphoid organs. 11,12 To demonstrate that the DKO-hu HSC mouse can support efficient HIV-1 infection with relevant immunopathogenesis, we show that CCR5 and CXCR4, the HIV-1 coreceptors, are both expressed on human T cells in central and peripheral lymphoid organs. DKO-hu HSC mice allow high plasma viremia with high levels of HIV-1 infection in lymphoid organs. Both CD4 ϩ CD45RO ϩ and CD4 ϩ CD45RO Ϫ T cells are productively infected in lymphoid organs. Human CD4 ϩ T cells are gradually depleted by HIV-1 in a dose-dependent manner. In addition, HIV-1 infection persists in infected DKO-hu HSC mice for at least 19 weeks, with recoverable infectious HIV-1 in lymphoid tissues. Materials and methods Construction of DKO-hu HSC mice with human CD34 ؉/؊ cells from cord blood or fetal liverHuman CD34 ϩ cells were isolated from cord blood (CB) or fetal liver (FL) tissues. FL CD34 ϩ (1 ϫ 10 6 ) or CB CD34 ϩ (1 ϫ 10 5 ) cells were injected intrahepatically into each newborn DKO mouse previously irradiated at 400 rad. 11 Human leukocytes (CD45 ϩ ) were analyzed for CD3, CD4, CD8, CD45RO, CD19, CCR5(2D7), and CXCR4(12G5) by fluorescenceactivated cell sorting (FACS). 13 HIV-1 infection and pathogenesis in DKO-hu HSC miceAt l...

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“…11 Human leukocytes (CD45 ϩ ) were analyzed for CD3, CD4, CD8, CD45RO, CD19, CCR5(2D7), and CXCR4(12G5) by fluorescenceactivated cell sorting (FACS). 13 …”

Section: Methodsmentioning

confidence: 99%

Section: Hiv-1 Infection and Pathogenesis In Dko-hu Hsc Micementioning

confidence: 99%

HIV-1 infection and pathogenesis in a novel humanized mouse model

Zhang

Kovalev

2006

Blood

127

136

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“…HIV infection of the human thymus is associated with thymic destruction and accelerated disease progression (42)(43)(44)(45)(46). Given the profound effects of IL-7 on the survival of human thymocytes, it is possible that IL-7 might prevent or attenuate HIV-mediated destruction of the thymus.…”

Section: Effects Of Il-7 On Hiv-infected and Uninfected Thymus In Scimentioning

confidence: 99%

Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice

Napolitano

Stoddart

Hanley

et al. 2003

The Journal of Immunology

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IL-7 is a critical component of thymopoiesis in animals and has recently been shown to play an important role in T cell homeostasis. Although there is increasing interest in the use of IL-7 for the treatment of lymphopenia caused by the HIV type 1, evidence that IL-7 may accelerate HIV replication has raised concerns regarding its use in this setting. We sought to identify the effects of IL-7 on human thymocyte survival and to determine the impact of IL-7 administration on in vivo HIV infection of the human thymus. Using in vitro analysis, we show that IL-7 provides potent anti-apoptotic and proliferative signals to early thymocyte progenitors. Analysis of CD34+ subpopulations demonstrates that surface IL-7 receptor is expressed on most CD34highCD5+CD1a− thymocytes and that this subpopulation appears to be one of the earliest maturation stages responsive to the effects of IL-7. Thus, IL-7 provides survival signals to human thymocytes before surface expression of CD1a. CD4+CD8+ thymocytes are relatively unresponsive to IL-7, although IL-7 protects these cells from dexamethasone-induced apoptosis. IL-7 has a predominantly proliferative effect on mature CD4+CD3+CD8− and CD8+CD3+CD4− thymocytes. In contrast to the in vitro findings, we observe that in vivo administration of IL-7 to SCID-hu Thy/Liv mice does not appear to enhance thymocyte survival nor does it appear to accelerate HIV infection. Given the growing interest in the use of IL-7 for the treatment of human immunodeficiency, these findings support additional investigation into its in vivo effects on thymopoiesis and HIV infection.

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“…Only thymocyte samples with good viability Indeed, in SCID-hu mouse studies, [10][11][12][13][14] HIV-1 infection was (Ͼ95%) were used. Portions of each sample were used for the shown to cause drastic destruction of grafted human thy-CT assay, and to determine antigen (Ag) profiles and proliferatmuses.…”

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confidence: 99%

“…[10][11][12][13][14] These accumulated findings could conceivably be related to rapid thymic cell death phenomenon without MHC restriction to, or virus replication in, the targets by contact with some the in vitro rapid thymic cell death phenomenon we observed, and indeed they are all relevant to the better understanding HIV-1 carrier clones (notably CD8 + clones) specific to TdT + CD4 + CD8 + and/or TdT + CD4 + thymic T cell targets, of HIV-1 pathogenesis. The present in vitro study, nonetheless, demonstrates clearly including an autologous combination of parental DP cells (HPB-ALL) and their CD8 SP HIV-1 carrier progeny clones that at the clonal level, HIV-1 carrier T cell clones, which are likely present in vivo, 8,[41][42][43][44] are responsible for the profound (HPB-ALL/HIV and HPB-ALL/HIV C1) (Tables 1 and 2).…”

mentioning

confidence: 99%