HIV induces thymus depletion in vivo

Bonyhadi, Mark; Rabin, Linda; Salimi, Suzan; Brown, D. A.; Kosek, Jon C.; McCune, Joseph M.; Kaneshima, Hideto

doi:10.1038/363728a0

Cited by 359 publications

(237 citation statements)

References 27 publications

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“…Our results are supportive of the results found in the SCID-hu thy/liv model that suggested HIV also inhibited early stages of thymocyte maturation [30]. Thus, HIV disrupts thymopoiesis by both direct infection of thymocytes as well as thymic epithelial dysfunction and destruction either through direct infection or a bystander inflammatory process, resulting in depletion of thymocytes and decreased de novo mature T cell generation [19][20][21][22][23]. Ultimate proof of thymopoietic potential in HIV infection will come from examination of thymopoiesis of HIV-infected thymuses from patients with AIDS and in clinical trials.…”

Section: Discussionsupporting

confidence: 80%

“…In addition there were clusters of HIV-infected CD34 + stem cells identified in the subcortical regions of these thymuses. HIV also disrupts thymopoiesis by direct infection of thymocytes [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Utilizing the SCID-hu thy/liv model that was then challenged with HIV-1, investigators demonstrated that thymopoiesis was impaired by direct infection of thymocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Antibody crossreactive to core p17 and p24 HIV antigens and thymic epithelial proteins has been observed in the HIV-infected thymus, suggesting an autoimmune component to HIV damage. In addition are the observations that human fetal thymus/liver organs transplanted into severe-combined immunodeficient (SCID) mice (SCID-hu thy/liv) in in vitro human models of thymopoiesis demonstrate that both HIVinfected thymocytes and T cells induce thymic epithelial cell injury [13][14][15][16][17][18][19][20][21][22][23]. Abnormal thymic epithelia synthetic function has been demonstrated by decreased synthesis of thymic hormones, such as thymosin-α1 and thymosin-β4 [14].…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Thymopoiesis of CD34⁺Cell Maturation by HIV‐1 in an In Vitro CD34⁺Cell and Thymic Epithelial Organ Culture Model

et al. 1999

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The mechanisms by which HIV-1 affects thymopoiesis were determined by preincubating CD34 + cells or cultured thymic epithelial (CTE) cells with lymphotropic (T-) and monotropic (M-) strains of HIV-1 in an in vitro CTE organ and CD34 + cell coculture model that allows for analysis of development of thymocytes and mature T cells.When purified CD34 + cells were precultured with either T-or M-tropic strains of HIV-1, thymopoiesis was impaired in a two-week coculture manifested by decreased cell number of thymocytes generated. However, the percentages of thymocyte subpopulations were comparable to control uninfected cocultures. Furthermore, HIV infection of thymocytes was predominantly observed in the CD44 + CD3 -population. However, in a four-week coculture experiment, HIV infection and depletion of more mature thymocytes were also observed.When CTE cells were preincubated with T-and Mtropic strains of HIV before addition of CD34 + cells, the number of thymocytes and subpopulations of thymocytes at early and later stages of maturation were markedly decreased. Furthermore, CD34 + and CD44 + CD3 -cells become HIV-infected.In summary, HIV-1 infection inhibited thymocyte maturation at early stages of thymocyte maturation CD44 + CD25 -CD3 -. In addition, HIV also depleted later stages of CD4 + thymocyte subpopulations.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Thymopoiesis of CD34⁺Cell Maturation by HIV‐1 in an In Vitro CD34⁺Cell and Thymic Epithelial Organ Culture Model

et al. 1999

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“…In this regard, experimental infection of mice with a number of bacteria (Listeria monocytogenes [6], Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Streptococcus pneumoniae [7]), viruses (murine cytomegalovirus [8], murine leukemia virus [9], HIV [10], and mouse hepatitis virus [11]), and protozoa (Toxoplasma gondii [12], and Trypanosoma cruzi) induces a severe lymphocytopaenia and marked thymus atrophy and loss of cortical lymphocytes. In addition, certain bacterial products and toxins, such as lipopolysaccharide (LPS) [13], enterotoxigenic E. coli enterotoxin [14] and mycobacterial cord factor (trehalos 6,6′-dimycolate) [15], also cause severe thymus damage.…”

Section: Introductionmentioning

confidence: 99%

Low dose aerosol infection of mice with virulent type A Francisella tularensis induces severe thymus atrophy and CD4+CD8+ thymocyte depletion

Chen

KuoLee

Austin

et al. 2005

Microbial Pathogenesis

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Francisella tularensis is a gram-negative facultative intracellular bacterium and the causative agent of tularemia. Two subspecies (type A and B strains) of the pathogen exist, the former being much more virulent than the latter for humans and other higher mammals. In this study, we examined the effect of virulent strains of F. tularensis infection on the thymus and thymocytes and the potential mechanisms involved. Low-dose aerosol exposure of C57BL/6 mice with type A, but not type B, F. tularensis caused severe reduction in thymus weight and destruction of thymocytes, particularly CD4 + CD8 + thymocytes, by day 4 after infection. The depletion of thymocytes was accompanied by a significant increase in circulating cortisone levels and could be partially prevented by adrenalectomy. Moreover, thymus atrophy and thymocyte depletion following infection were abolished in mice deficient in tumor necrosis factor receptors 1 and 2, but not in FasL-deficient mice. The severe destruction of the thymus and selective depletion of immature thymocytes during type A F. tularensis infection may represent a key pathogenic mechanism in tularemia and could hinder the development of an effective primary immune response against this highly virulent pathogen.

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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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HIV induces thymus depletion in vivo

Cited by 359 publications

References 27 publications

Inhibition of Thymopoiesis of CD34⁺Cell Maturation by HIV‐1 in an In Vitro CD34⁺Cell and Thymic Epithelial Organ Culture Model

Inhibition of Thymopoiesis of CD34⁺Cell Maturation by HIV‐1 in an In Vitro CD34⁺Cell and Thymic Epithelial Organ Culture Model

Low dose aerosol infection of mice with virulent type A Francisella tularensis induces severe thymus atrophy and CD4+CD8+ thymocyte depletion

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

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HIV induces thymus depletion in vivo

Cited by 359 publications

References 27 publications

Inhibition of Thymopoiesis of CD34+Cell Maturation by HIV‐1 in an In Vitro CD34+Cell and Thymic Epithelial Organ Culture Model

Inhibition of Thymopoiesis of CD34+Cell Maturation by HIV‐1 in an In Vitro CD34+Cell and Thymic Epithelial Organ Culture Model

Low dose aerosol infection of mice with virulent type A Francisella tularensis induces severe thymus atrophy and CD4+CD8+ thymocyte depletion

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

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Inhibition of Thymopoiesis of CD34⁺Cell Maturation by HIV‐1 in an In Vitro CD34⁺Cell and Thymic Epithelial Organ Culture Model

Inhibition of Thymopoiesis of CD34⁺Cell Maturation by HIV‐1 in an In Vitro CD34⁺Cell and Thymic Epithelial Organ Culture Model