Early Progression of Disease in HIV-Infected Infants with Thymus Dysfunction

Kourtis, Athena P.; Ibegbu, Christian; Nahmias, André J.; Lee, F K; Clark, William S.; Sawyer, Mary K.; Nesheim, Steven

doi:10.1056/nejm199611073351904

Cited by 175 publications

(127 citation statements)

References 32 publications

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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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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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“…Patients were assessed as fitting the thymic dysfunction phenotype by comparison of absolute CD4 and CD8 counts at the time of sample to previously published control patients (22). Patients fitting the TD criteria were defined as having absolute peripheral CD4 ϩ and CD8 ϩ T cell counts below the fifth percentile of HIV-1-uninfected controls born to HIV-1-infected mothers (15).…”

Section: Patient Cohortmentioning

confidence: 99%

“…In particular, we wished to determine whether the CD8 low phenotype might be associated with signs of thymic HIV-1 infection. Thus, we identified HIV-1-infected children with evidence of TD (defined as absolute peripheral CD4 ϩ and CD8 ϩ T cell counts below the fifth percentile of HIV-1-uninfected-controls born to HIV-1-infected mothers) (15,22). TD patients have been found to display a constellation of clinical characteristics (e.g., increased vulnerability to infections caused by viruses, fungi, and Pneumocystis carinii) similar to those found in children born with congenital thymic abnormalities (e.g., DiGeorge syndrome).…”

Section: Cd8 Low T Cells Are Also Observed In Hiv-1-infected Childrenmentioning

confidence: 99%

“…In children with perinatal HIV-1 disease, thymic infection is associated with low peripheral T cell counts of both the CD4 and CD8 lineages and with rapid disease progression. Patients with such "thymic dysfunction" (TD) represent a substantial number (ϳ25-30%) of all perinatally infected children and bear many clinical features in common with infants born with congenital thymic defects (15) In addition to the possibility of direct HIV-1 infection of thymocytes, qualitative defects in thymic maturation may also arise. Noncytopathic HIV-1 infection of thymic epithelial cells (TEC) or of thymic myeloid cells might result in HIV-1 peptides being presented in the context of host MHC class I (MHC I) or class II (MHC II) Ags, driving positive and/or negative selection in a nonphysiologic manner.…”

mentioning

confidence: 99%

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Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

Keir

Rosenberg

Sandberg

et al. 2002

The Journal of Immunology

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Infection with the HIV type 1 (HIV-1) can result both in depletion of CD4+ T cells and in the generation of dysfunctional CD8+ T cells. In HIV-1-infected children, repopulation of the peripheral T cell pool is mediated by the thymus, which is itself susceptible to HIV-1 infection. Previous work has shown that MHC class I (MHC I) molecules are strongly up-regulated as result of IFN-α secretion in the HIV-1-infected thymus. We demonstrate in this study that increased MHC I up-regulation on thymic epithelial cells and double-positive CD3−/intCD4+CD8+ thymocytes correlates with the generation of mature single-positive CD4−CD8+ thymocytes that have low expression of CD8. Treatment of HIV-1-infected thymus with highly active antiretroviral therapy normalizes MHC I expression and surface CD8 expression on such CD4−CD8+ thymocytes. In pediatric patients with possible HIV-1 infection of the thymus, a low CD3 percentage in the peripheral circulation is also associated with a CD8low phenotype on circulating CD3+CD8+ T cells. Furthermore, CD8low peripheral T cells from these HIV-1+ pediatric patients are less responsive to stimulation by Ags from CMV. These data indicate that IFN-α-mediated MHC I up-regulation on thymic epithelial cells may lead to high avidity interactions with developing double-positive thymocytes and drive the selection of dysfunctional CD3+CD8low T cells. We suggest that this HIV-1-initiated selection process may contribute to the generation of dysfunctional CD8+ T cells in HIV-1-infected patients.

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“…HIV-1-infected infants with T cell lymphopenia within the first 6 mo of life were more likely to progress rapidly to AIDS than were those with normal T cell levels (67). Thus, in children and young adults, disruption of the thymus by HIV-1 may result in reduced postthymic T cell pools (67)(68)(69).…”

Section: The Thymus In Hiv Infectionmentioning

confidence: 99%

The human thymus

Haynes

Hale

1998

Immunol Res

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The human thymus is a lymphoepithelial organ in which T cells develop during fetal life. After maturation and selection in the fetal thymic microenvironment, T cells emigrate to peripheral lymphoid tissues such as the spleen, gut, and lymph nodes, and establish the peripheral T cell repertoire. Although the thymus has enormous regenerative capacity during fetal development, the regenerative capacity of the human postnatal thymus decreases over time. With the advent of intensive chemotherapy regimens for a variety of cancer syndromes, and the discovery that infection with the Human Immunodeficiency Virus (HIV) leads to severe loss of CD4 + T cells, has come the need to understand the role of the human thymus in reconstitution of the immune system in adults. During a recent study of the thymus in HIV infection, we observed many CD8 + T cells in AIDS thymuses that had markers consistent with those of mature effector cytotoxic T cells usually found in peripheral immune tissues, and noted these CD8 + effector T cells were predominately located in a thymic zone termed the thymic perivascular space. This article reviews our own work on the thymus in HIV-1 infection, and discusses the work of others that, taken together, suggest that the thymus contains peripheral immune cell components not only in the setting of HIV infection, but also in myasthenia gravis, as well as throughout normal life during the process of thymus involution. Thus, the human thymus can be thought of as a chimeric organ comprised of both central and peripheral lymphoid tissues. These observations have led us to postulate that the thymic epithelial atrophy and decrease in thymopoiesis that occurs in myasthenia gravis, HIV-I infection, and thymic involution may in part derive from cytokines or other factors produced by peripheral immune cells within the thymic perivascular space.

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Early Progression of Disease in HIV-Infected Infants with Thymus Dysfunction

Cited by 175 publications

References 32 publications

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

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

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

The human thymus

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