Replication of cytomegalovirus in human thymic epithelial cells

Numazaki, Kei; Destephano, L; Wong, Inés; Goldman, Hy; Spira, Bonnie; Wainberg, Mark A.

doi:10.1007/bf00203304

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…Indeed, there is supportive precedent in the literature for this, as previous studies have documented that CMV can infect thymic epithelium and that activated and effector T cells can directly infiltrate and damage the thymus. 43,[61][62][63] Moreover, a previous study of young adults, thymectomized as children, showed that the combination of the lack of thymic function and CMV infection lead to dramatic changes in T-cell homeostasis. 55 These data suggest the novel hypothesis that CMV-associated thymic damage may be one of the contributory mechanisms for the immune compromise that accompanies CMV reactivation after transplant.…”

Section: Discussionmentioning

confidence: 99%

“…40,41 These results are consistent with thymic compromise in CMV-reactivating patients, an observation that has previously been shown in humanized murine models. 42,43 Although Figures 2B and 7A-B document the impact of CMV reactivation on Tnaive reconstitution, when patients were dichotomized by the presence or absence of GVHD, no such correlation with Tnaive reconstitution was observed ( Figure 7C-E).…”

Section: Reactivation Drives Antigen-specific T-cell Clonal Expanmentioning

confidence: 94%

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CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

Suessmuth

Mukherjee

Watkins

et al. 2015

Blood

153

148

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Key Points• CMV reactivation fundamentally resets posttransplant CD8 reconstitution, resulting in massive expansion of CMVspecific CD8 Tem.• CMV reactivation is associated with defects in the underlying TCRb immune repertoire.Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B high / CD28 low /CD57 high /CD8 1 effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31 1 /CD4 1 putative thymic emigrants. T-cell receptor b (TCRb) deep sequencing revealed a striking contraction of CD8 1 Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials. gov as #NCT01012492. (Blood. 2015;125(25):3835-3850)

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Section: Discussionmentioning

confidence: 99%

Section: Reactivation Drives Antigen-specific T-cell Clonal Expanmentioning

confidence: 94%

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

Suessmuth

Mukherjee

Watkins

et al. 2015

Blood

153

148

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“…After human fetal brain tissue dispersion, the resulting cell suspension was filtered through sterile nylon mesh (100 ,um) and centrifuged at 1,000 x g for 10 min. Cells were resuspended in a hormonally defined D-MEM medium (23), plated onto 9-mm poly-L-lysine-coated (Sigma) coverslips or tissue culture flasks, and maintained in this medium for 5 to 7 days. The vessels were shaken to dislodge nonadherent cells, which were removed by pipetting.…”

Section: Methodsmentioning

confidence: 99%

“…The vessels were shaken to dislodge nonadherent cells, which were removed by pipetting. The adherent population consisted almost entirely of astrocytes and was grown in D-MEM/HAMF-12 medium supplemented with 10% hiFCS (23 (24,33).…”

Section: Methodsmentioning

confidence: 99%

Effect of 3'-azido-3'-deoxythymidine on human immunodeficiency virus type 1 replication in human fetal brain macrophages

Geleziunas

Arts

Boulerice

et al. 1993

Antimicrob Agents Chemother

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We investigated whether cells derived from the fetal central nervous system can support productive infection by a human immunodeficiency virus type 1 (HIV-1) isolate termed UHC-1, produced by a cellular clone derived from HIV-1 strain HIV-IIIB chronically infected U-937 promonocytic cells, and what the effect of nucleoside analogs might be on viral replication in this system. Fractionation of human fetal brain tissue into two different populations, enriched for either astrocytes or macrophages, showed that only the latter were able to support productive UHC-1 replication and generation of detectable progeny virus. Pretreatment of fetal brain macrophages with either of two nucleoside analogs, 3'-azido-3'-deoxythymidine (AZT) or the (-) enantiomer of 2'-deoxy-3'-thiacytidine, efficiently blocked production of progeny virus. Generation of unintegrated proviral DNA and HIV-1 transcripts were inhibited by pretreatment of fetal brain macrophages with 1 microM AZT. Administration of AZT at 24 h postinfection led to a slight reduction in viral transcript levels and viral progeny production by day 15 postinfection; however, brain macrophages under these conditions did not contain detectable amounts of unintegrated viral DNA. These results suggest that AZT may interfere with the accumulation of unintegrated HIV-1 DNA in brain macrophages. This is the first demonstration that nucleoside analogs are able to block HIV-1 replication in primary cultures of brain cells.

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“…The broad range of cell types that HCMV is known to infect supports the idea that a ubiquitously expressed molecule, such as MHC I, may be the receptor for HCMV. For example, HCMV infects human fibroblast (Weller, 1971), human thymic epithelial cells (Numazaki et aL, 1989), human lymphocytes (Einhorn & Ost, 1984), certain peripheral blood mononuclear cells (Soderberg et al, 1993a) and human brain capillary endothelial cells (Lathey et al, 1990;Poland et al, 1990). Several studies with routine cytomegalovirus also suggested that MHC I molecules play a role in initiating infection (Chalmer et al, 1977;Price et al, 1990;Wykes et al, 1992Wykes et al, , 1993.…”

confidence: 99%

Replication of human cytomegalovirus in cells deficient in beta2-microglobulin gene expression

Qian¹,

Trymbulak

Tatake

et al. 1994

Journal of General Virology

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To study the roles offl2-microglobulin (fl~-m) and major histocompatibility complex (MHC) class I expression in human cytomegalovirus (HCMV) infection, the ability of HCMV strain AD-169 to infect and replicate in a human melanoma cell line (FO-1), which is fl2-mdeficient and cannot express MHC class I on its cell surface, was examined. Susceptibility of FO-1 cells was compared with human foreskin fibroblasts (HFF) and FO-1H cells (FO-1 cells that have been transfected with the human fl2-m gene, restoring MHC I expression on the cell surface). As judged by the HCMV immediate early 1 (IE-1) antigen expression, HCMV was able to infect FO-1 cells, although somewhat less efficiently than HFF. However, the expression of HCMV late (L) antigen and the production of virus was significantly less for FO-1 cells than for HFF. Analysis of the FO-1H transfectants revealed that expression of IE-1 and L HCMV antigens was comparable to FO-1 cells, which lack MHC I. Treatment of FO-1 and FO-1H cells with sodium butyrate prior to inoculation did not alter the expression ofMHC I in either cell type, but did increase susceptibility of both cell types to HCMV infection, as well as the expression of L antigens and production of virus. These studies indicate that HCMV infection of FO-1 cells is independent of fl2-m and MHC class I expression.Human cytomegalovirus (HCMV) is a herpesvirus that causes significant diseases in immunocompromised individuals and in congenitally infected newborns (Weller, 1971;Adler, 1990;Betts & Hanshaw, 1977). To understand the interactions of a virus with a host, it is crucial to characterize the early interactions with target cells. A number of receptors have been identified for human pathogenic viruses, including CR2 for Epstein-Barr virus (Fingeroth et al., 1984;Nemerow et al., 1985), CD4 for human immunodeficiency virus (Dalgleish et al., 1984) and ICAM-1 for rhinoviruses (Staunton et al., 1989). Although our understanding of HCMV infection of cells has significantly increased, the mechanisms involved in initiating HCMV infection remain difficult to characterize. A number of candidates have been considered as the cellular receptors that mediate HCMV infection (Taylor & Cooper, 1989;Cooper et al., 1991 ;Nowlin et al., 1991 ;Compton et al., 1992Compton et al., , 1993Keay et al., 1989).Previous reports that HCMV avidly associates with fl2-microglobulin (fl2-m) led to the hypothesis that HCMV may use the major histocompatibility complex (MHC) class I complex as one route to initiate infection (Grundy, 1990). The MHC I molecules are glycosylated transmembrane polypeptides, which are non-covalently associated with the non-glycosylated protein, fl~-m, fl2-m association is necessary for the processing, transport and expression of the MHC I antigens on the cell surface (Cox et al., 1990;Sege et al., 1981). To examine the role of fl2-m and MHC I in HCMV infection, the FO-1 cell line, which is unable to express MHC I molecules on the cell surface owing to a deletion mutation of the fl2-m gene (D'urso et al., 1990)...

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Replication of cytomegalovirus in human thymic epithelial cells

Cited by 13 publications

References 38 publications

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

Effect of 3'-azido-3'-deoxythymidine on human immunodeficiency virus type 1 replication in human fetal brain macrophages

Replication of human cytomegalovirus in cells deficient in beta2-microglobulin gene expression

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