Human Immunodeficiency Virus Type 1 Vpr Impairs Dendritic Cell Maturation and T-Cell Activation: Implications for Viral Immune Escape

Majumder, Biswanath; Janket, Michelle L.; Schafer, Elizabeth A.; Schaubert, Keri L.; Huang, Xiao Li; Kan‐Mitchell, June; Rinaldo, Charles R.; Ayyavoo, Velpandi

doi:10.1128/jvi.79.13.7990-8003.2005

Cited by 107 publications

(109 citation statements)

References 71 publications

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“…However, we show that programming of the activated virusspecific CD8 + T cells in the LN is not sufficient to maintain their expansion and survival at the periphery or the effector site, which is the lungs in the case of influenza A infections. The DC and CD28 requirement of effector CD8 + T cells has important implications for antiviral and antitumor effector CD8 + T cell responses as one of the immune evasion mechanisms used by viruses (19)(20)(21)(22) and tumors (23,24) is the suppression of DC maturation and inhibition of expression of CD28 costimulatory ligands CD80 and CD86. This requirement for CD28 signaling by effector cells may also contribute to the immune dysfunction found in chronic infections such as HIV infection and aging, where CD28…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo

Dolfi

Duttagupta

Boesteanu

et al. 2011

The Journal of Immunology

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Although much is known about the initiation of immune responses, much less is known about what controls the effector phase. CD8+ T cell responses are believed to be programmed in lymph nodes during priming without any further contribution by dendritic cells (DCs) and Ag. In this study, we report the requirement for DCs, Ag, and CD28 costimulation during the effector phase of the CD8+ T cell response. Depleting DCs or blocking CD28 after day 6 of primary influenza A virus infection decreases the virus-specific CD8+ T cell response by inducing apoptosis, and this results in decreased viral clearance. Furthermore, effector CD8+ T cells adoptively transferred during the effector phase fail to expand without DC, CD28 costimulation, and cognate Ag. The absence of costimulation also leads to reduced survival of virus-specific effector cells as they undergo apoptosis mediated by the proapoptotic molecule Bim. Finally, IL-2 treatment restored the effector response in the absence of CD28 costimulation. Thus, in contrast to naive CD8+ T cells, which undergo an initial Ag-independent proliferation, effector CD8+ T cells expanding in the lungs during the effector phase require Ag, CD28 costimulation, and DCs for survival and expansion. These requirements would greatly impair effector responses against viruses and tumors that are known to inhibit DC maturation and in chronic infections and aging where CD28−/− CD8+ T cells accumulate.

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Section: Discussionmentioning

confidence: 99%

Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo

Dolfi

Duttagupta

Boesteanu

et al. 2011

The Journal of Immunology

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“…To demonstrate that TV9 is naturally processed and presented by APCs, this reactivity was sought in cultures derived from purified circulating CD8 ϩ T cells primed with DCs transduced with a vesicular stomatitis virus glycoprotein-pseudotyped pNL4-3 virus (pNL4-3 E Ϫ ) encoding Gag and Pol (57). Transduction was verified by staining for intracellular Gag p24.…”

Section: Tv9 Is Naturally Processed and Presented In The Context Of Hmentioning

confidence: 99%

“…Production in HEK293T cells was described previously (57). Virus titers were measured using the HIV-1 reporter cell line cMAGI (AIDS Research and Reference Reagent Program, National Institutes of Health).…”

Section: Hiv-1 Vector and DC Transductionmentioning

confidence: 99%

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

Schaubert

Price

Frahm

et al. 2007

The Journal of Immunology

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HLA-A2-restricted CTL responses to immunodominant HIV-1 epitopes do not appear to be very effective in the control of viral replication in vivo. In this study, we studied human CD8+ T cell responses to the subdominant HLA-A2-restricted epitope TV9 (Gag p2419–27, TLNAWVKVV) to explore the possibility of increasing its immune recognition. We confirmed in a cohort of 313 patients, infected by clade B or clade C viruses, that TV9 is rarely recognized. Of interest, the functional sensitivity of the TV9 response can be relatively high. The potential T cell repertoires for TV9 and the characteristics of constituent clonotypes were assessed by ex vivo priming of circulating CD8+ T cells from healthy seronegative donors. TV9-specific CTLs capable of suppressing viral replication in vitro were readily generated, suggesting that the cognate T cell repertoire is not limiting. However, these cultures contained multiple discrete populations with a range of binding avidities for the TV9 tetramer and correspondingly distinct functional dependencies on the CD8 coreceptor. The lack of dominant clonotypes was not affected by the stage of maturation of the priming dendritic cells. Cultures primed by dendritic cells transduced to present endogenous TV9 were also incapable of clonal maturation. Thus, a diffuse TCR repertoire appeared to be an intrinsic characteristic of TV9-specific responses. These data indicate that subdominance is not a function of poor immunogenicity, cognate TCR repertoire availability, or the potential avidity properties thereof, but rather suggest that useful responses to this epitope are suppressed by competing CD8+ T cell populations during HIV-1 infection.

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“…HEK-293T cells (2×10 6 per plate) were cotransfected with 15μg of HIV-1 proviral constructs by the calcium phosphate precipitation method (Majumder et al, 2005). Cell free supernatant was collected 72 hours posttransfection and assayed for virus production by p24 ELISA.…”

Section: Plasmids and Virus Infectionmentioning

confidence: 99%

Human immunodeficiency virus (HIV-1) Vpr induced downregulation of NHE1 induces alteration in intracellular pH and loss of ERM complex in target cells

Janket¹,

DeRicco²,

Borowski³

et al. 2007

Virus Research

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Human Immunodeficiency Virus type 1 (HIV-1) Vpr is known to dysregulate host cellular functions through its interaction with cellular proteins. Using a protein array we assessed Vpr-mediated differential regulation of host cellular proteins expression. Results demonstrated that Vpr differentially regulated host factors that are involved in functions such as cell proliferation, differentiation and apoptosis. One of the most highly downregulated proteins attained was the sodium hydrogen exchanger, isoform 1 (NHE1), which showed a significant (60%) decrease in HIV-1 vpr (+) virus infected cells as compared to HIV-1 vpr(−) virus infected control. NHE1 downregulation further led to acidification of cells and was directly correlated with loss of ezrin, radixin and moesin (ERM) protein complex and decreased AKT phosphorylation. Vpr-mediated NHE1 dyregulation is in part through GR pathway as GR antagonist, mifepristone reversed Vpr-induced NHE1 downregulation.

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Human Immunodeficiency Virus Type 1 Vpr Impairs Dendritic Cell Maturation and T-Cell Activation: Implications for Viral Immune Escape

Cited by 107 publications

References 71 publications

Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo

Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

Human immunodeficiency virus (HIV-1) Vpr induced downregulation of NHE1 induces alteration in intracellular pH and loss of ERM complex in target cells

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