Distinct Transcriptional Profiles in Ex Vivo CD4+and CD8+T Cells Are Established Early in Human Immunodeficiency Virus Type 1 Infection and Are Characterized by a Chronic Interferon Response as Well as Extensive Transcriptional Changes in CD8+T Cells

Hyrcza, Martin; Kovacs, Colin; Loutfy, Mona; Halpenny, Roberta; Heisler, Lawrence E.; Yang, Stuart; Wilkins, Olivia; Ostrowski, Mario; Der, Sandy D.

doi:10.1128/jvi.01552-06

Cited by 173 publications

(167 citation statements)

References 41 publications

Supporting

Mentioning

154

Contrasting

Order By: Relevance

“…Increased IFN-a activity (20)(21)(22) and elevated production of IFN-a in PBMC and plasmacytoid dendritic cell cultures is a characteristic of HIV infection (23) and is associated with both CD4 + T cell depletion and disease progression (21). IFN-a is an essential mediator of the innate immune response, and its ex-pression is rapidly upregulated in response to viral pathogens, reflecting its potent antiviral activity.…”

mentioning

confidence: 99%

“…Activation of the IFN-a receptor triggers a signaling cascade that initially includes the tyrosine kinases, Tyk2 and Jak1, and eventually results in activation of transcription factor complexes, such as IFN-stimulated gene factor 3 and phosphorylation and dimerization of STAT molecules, which translocate to the cell nucleus and regulate the expression of numerous ISG. Untreated HIV infection is associated with increased expression of mRNA of several ISG in monocytes (24) and T cells (20).…”

mentioning

confidence: 99%

See 1 more Smart Citation

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

Cha

Jong

French

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

To determine whether IFN-α is a cause of the T cell hyperactivation and IL-7 signaling pathway defects that are observed in some HIV patients receiving antiretroviral therapy, we have investigated the effect of IFN-α on the proliferation of CD4+ and CD8+ T cells from healthy donors (n = 30) and treated HIV+ donors (n = 20). PBMC were cultured for 7 d with staphylococcal enterotoxin B or IL-7 in the absence or presence of 100 U/ml IFN-α8. Total and naive CD4+ and CD8+ T cells were assessed for proliferation (via Ki67 expression), CD127 expression, and phosphorylated STAT5 levels using flow cytometry. IFN-α significantly enhanced activation-induced proliferation (via staphylococcal enterotoxin B stimulation) but inhibited homeostatic proliferation (IL-7 induced) of CD4+ and CD8+ T cells. Both of these effects may adversely affect CD4+ T cell homeostasis in HIV patients. CD127 expression was increased in both healthy and HIV+ donors following culture with IFN-α8, and levels of IL-7–induced phosphorylated STAT5 were increased by IFN-α8 in healthy donors only. Hence, the inhibitory effects of IFN-α on IL-7–induced proliferation of CD4+ T cells are unlikely to be mediated by downregulation of CD127 expression or inhibition of STAT5 phosphorylation. These data suggest that increased IFN-α activity may promote the loss of T cells by accelerating cell turnover and activation-induced cell death while decreasing the renewal of T cells by inhibiting the proliferative effect of IL-7.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

Cha

Jong

French

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The gene expression profiles derived from twenty-one studies revealed a strong statistically-significant negative correlation (score: 62) with the expression pattern of zidovudine. Figure 4 displays a comparison of gene expressions between the query experiment and the experiment "CD8+ T cells from chronic HIV infection patients _vs_ negative control" listed under the study "HIV-infected individuals with various clinical stages of HIV infection" performed by Hyrcza et al [16]. Since the protocol correctly predicted that zidovudine could treat HIV, its intended target, this finding serves as a valuable result to prove the efficacy of this protocol.…”

Section: Negatively-correlated Diseasesmentioning

confidence: 99%

Demonstration Study: A Protocol to Combine Online Tools and Databases for Identifying Potentially Repurposable Drugs

Chattopadhyay¹,

Ganapathiraju

2017

Data

View full text Add to dashboard Cite

Abstract:Traditional methods for discovery and development of new drugs can be very time-consuming and expensive processes because they include several stages, such as compound identification, pre-clinical and clinical trials before the drug is approved by the U.S. Food and Drug Administration (FDA). Therefore, drug repurposing, namely using currently FDA-approved drugs as therapeutics for other diseases than what they are originally prescribed for, is emerging to be a faster and more cost-effective alternative to current drug discovery methods. In this paper, we have described a three-step in silico protocol for analyzing transcriptomics data using online databases and bioinformatics tools for identifying potentially repurposable drugs. The efficacy of this protocol was evaluated by comparing its predictions with the findings of two case studies of recently reported repurposed drugs: HIV treating drug zidovudine for the treatment of dry age-related macular degeneration and the antidepressant imipramine for small-cell lung carcinoma. The proposed protocol successfully identified the published findings, thus demonstrating the efficacy of this method. In addition, it also yielded several novel predictions that have not yet been published, including the finding that imipramine could potentially treat Severe Acute Respiratory Syndrome (SARS), a disease that currently does not have any treatment or vaccine. Since this in silico protocol is simple to use and does not require advanced computer skills, we believe any motivated participant with access to these databases and tools would be able to apply it to large datasets to identify other potentially repurposable drugs in the future.

show abstract

“…12 A total of 40 genechips were available, including genechips from uninfected samples, nonprogressive HIV infection samples, chronic infection HIV samples, and acute HIV infection samples (five genechips from CD4 + cells and five genechips from CD8 + cells, respectively). The annotations of chips were downloaded from the GPL96 platform (Affymetrix Human Genome U133A Array).…”

Section: Affymetrix Microarray Datamentioning

confidence: 99%

“…ncbi.nlm.nih.gov/COG) 16 has been incepted as a phylogenetic classification of proteins from complete genomes. All the DEGs were aligned to the COG database through the Basic Local Alignment Search Tool (BLASTx) 12,17 for functional annotation with the threshold of E-value < 1e-05. The functions of DEGs in CD4 + and CD8 + T cells were observed directly at any stage.…”

Section: Functional Classificationmentioning

confidence: 99%

Comparison of Transcriptional Profiles Between CD4⁺ and CD8⁺ T Cells in HIV Type 1-Infected Patients

Ye²,

Han³

et al. 2014

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

The CD4+ /CD8 + T cell ratio is altered when HIV-1 infects the human immune system. However, the exact mechanisms of how CD4+ and CD8 + T cells participate in HIV infection are still unknown. This study used bioinformatics methods to compare the transcriptional profiles between CD4+ and CD8 + T cells in HIV-1-infected patients in order to explore the potential molecular mechanisms of CD4 + and CD8 + T cells in HIV-1 infection. We found that expression patterns of differentially expressed genes (DEG) in CD4 + T cells were dramatically different from those in CD8 + T cells. We also constructed protein-protein interaction (PPI) networks to extract functional modules at each stage, and found that some of the important genes such as BRCA1 were central hubs of the modules. Finally, we applied functional annotation to the modules and found that CD4 + /CD8 + T cells played critical roles in regulating the cell cycle and other cellular pathways. Thus, this study would greatly further our understanding of the roles of T cells in HIV infection, and provide potential clues for developing AIDS vaccines in the future.

show abstract

Distinct Transcriptional Profiles in Ex Vivo CD4⁺and CD8⁺T Cells Are Established Early in Human Immunodeficiency Virus Type 1 Infection and Are Characterized by a Chronic Interferon Response as Well as Extensive Transcriptional Changes in CD8⁺T Cells

Cited by 173 publications

References 41 publications

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

Demonstration Study: A Protocol to Combine Online Tools and Databases for Identifying Potentially Repurposable Drugs

Comparison of Transcriptional Profiles Between CD4⁺ and CD8⁺ T Cells in HIV Type 1-Infected Patients

Contact Info

Product

Resources

About

Distinct Transcriptional Profiles in Ex Vivo CD4+and CD8+T Cells Are Established Early in Human Immunodeficiency Virus Type 1 Infection and Are Characterized by a Chronic Interferon Response as Well as Extensive Transcriptional Changes in CD8+T Cells

Cited by 173 publications

References 41 publications

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

Demonstration Study: A Protocol to Combine Online Tools and Databases for Identifying Potentially Repurposable Drugs

Comparison of Transcriptional Profiles Between CD4+ and CD8+ T Cells in HIV Type 1-Infected Patients

Contact Info

Product

Resources

About

Distinct Transcriptional Profiles in Ex Vivo CD4⁺and CD8⁺T Cells Are Established Early in Human Immunodeficiency Virus Type 1 Infection and Are Characterized by a Chronic Interferon Response as Well as Extensive Transcriptional Changes in CD8⁺T Cells

Comparison of Transcriptional Profiles Between CD4⁺ and CD8⁺ T Cells in HIV Type 1-Infected Patients