Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion.

Schnittman, Steven M.; Denning, Stephen M.; Greenhouse, Jack; Justement, J. Shawn; Baseler, Michael; Kurtzberg, Joanne; Haynes, Barton F.; Fauci, Anthony S.

doi:10.1073/pnas.87.19.7727

Cited by 113 publications

(67 citation statements)

References 33 publications

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“…Others have reported infection of thymic TCR␥␦ clones in vitro (59,60), suggesting the potential for direct infection by HIV-1 in vivo. For the most part, TCR␥␦ cells in the periphery do not express CD4, and thus the only point at which TCR␥␦ ϩ cells are naturally susceptible to HIV-1 infection is during development in the thymus when CD4 is expressed (23).…”

Section: Discussionmentioning

confidence: 99%

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

Gurney

Yang

Wilson

et al. 2002

The Journal of Immunology

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The vast diversity of the T cell repertoire renders the adaptive immune response capable of recognizing a broad spectrum of potential antigenic peptides. However, certain T cell rearrangements are conserved for recognition of specific pathogens, as is the case for TCRγδ cells. In addition, an immunoregulatory class of T cells expressing the NK receptor protein 1A (CD161) responds to nonpeptide Ags presented on the MHC-like CD1d molecule. The effect of HIV-1 infection on these specialized T cells in the thymus was studied using the SCID-hu mouse model. We were able to identify CD161-expressing CD3+ cells but not the CD1d-restricted invariant Vα24/Vβ11/CD161+ NK T cells in the thymus. A subset of TCRγδ cells and CD161-expressing thymocytes express CD4, CXCR4, and CCR5 during development in the thymus and are susceptible to HIV-1 infection. TCRγδ thymocytes were productively infectable by both X4 and R5 virus, and thymic HIV-1 infection induced depletion of CD4+ TCRγδ cells. Similarly, CD4+CD161+ thymocytes were depleted by thymic HIV-1 infection, leading to enrichment of CD4−CD161+ thymocytes. Furthermore, compared with the general CD4-negative thymocyte population, CD4−CD161+ NK T thymocytes exhibited as much as a 27-fold lower frequency of virus-expressing cells. We conclude that HIV-1 infection and/or disruption of cells important in both innate and acquired immunity may contribute to the overall immune dysfunction seen in HIV-1 disease.

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Section: Discussionmentioning

confidence: 99%

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

Gurney

Yang

Wilson

et al. 2002

The Journal of Immunology

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“…In vitro studies have shown that HIV-1 can infect thymocytes from uninfected subjects, and in vivo studies in the SCID-hu chimera model have shown that immature thymocytes are infected by HIV-1 and implicate HIV as the direct (3)(4)(5) and indirect (6, 7) cause of thymocyte death. Although information on infection of thymocytes in vivo is limited, a report analyzing thymic tissue obtained from an infant with perinatal HIV-1 infection demonstrated infection in immature thymocytes (1).…”

mentioning

confidence: 99%

Mechanisms Associated with Thymocyte Apoptosis Induced by Simian Immunodeficiency Virus

Rosenzweig¹,

Connole²,

Forand-Barabasz³

et al. 2000

The Journal of Immunology

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Despite considerable research, the mechanisms by which HIV disrupts thymic function remain controversial. We have described the phenotypic changes that occur in the thymus of SIV-infected macaques during acute SIV infection. In this study, we analyzed the effects of SIV infection on apoptotic pathways in thymic tissue from newborn macaques infected with SIV. Thymocyte apoptosis was accompanied by a modest increase in surface Fas expression, a profound decrease in the frequency of bcl-2-positive cells, as well as the amount of bcl-2 per cell. With control of viral replication, levels of bcl-2 and Fas returned to baseline together with a return to basal levels of apoptosis. In the thymus, SIV infection resulted in depletion of CD4+CD8+ thymocytes, an increase in apoptosis of thymocytes, and a down-regulation of MHC class I molecules. These changes peaked 14–21 days after infection at or just after peak viremia. This data further suggests disruption of the antiapoptotic pathway regulated by bcl-2 plays a critical role in SIV-induced apoptosis of thymocytes.

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“…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%

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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Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion.

Abstract: Individuals infected by the human immunodeficiency virus type 1 (IV-i) demonstrate progressive de-

Cited by 113 publications

References 33 publications

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

Mechanisms Associated with Thymocyte Apoptosis Induced by Simian Immunodeficiency Virus

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

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Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion.

Abstract: Individuals infected by the human immunodeficiency virus type 1 (IV-i) demonstrate progressive de-

Cited by 113 publications

References 33 publications

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

Mechanisms Associated with Thymocyte Apoptosis Induced by Simian Immunodeficiency Virus

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

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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