Identification of molecular sub-networks associated with cell survival in a chronically SIVmac-infected human CD4+ T cell line

Feng Q. He, Ulrike Sauermann, Christiane Beer, Silke Winkelmann, Zheng Yu, Sieghart Sopper, An Ping Zeng, Manfred Wirth*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Background: The deciphering of cellular networks to determine susceptibility to infection by HIV or the related simian immunodeficiency virus (SIV) is a major challenge in infection biology. Results: Here, we have compared gene expression profiles of a human CD4+ T cell line at 24 h after infection with a cell line of the same origin permanently releasing SIVmac. A new knowledge-based-network approach (Inter-Chain-Finder, ICF) has been used to identify sub-networks associated with cell survival of a chronically SIV-infected T cell line. Notably, the method can identify not only differentially expressed key hub genes but also non-differentially expressed, critical, 'hidden' regulators. Six out of the 13 predicted major hidden key regulators were among the landscape of proteins known to interact with HIV. Several sub-networks were dysregulated upon chronic infection with SIV. Most prominently, factors reported to be engaged in early stages of acute viral infection were affected, e.g. entry, integration and provirus transcription and other cellular responses such as apoptosis and proliferation were modulated. For experimental validation of the gene expression analyses and computational predictions, individual pathways/sub-networks and significantly altered key regulators were investigated further. We showed that the expression of caveolin-1 (Cav-1), the top hub in the affected protein-protein interaction network, was significantly upregulated in chronically SIV-infected CD4+ T cells. Cav-1 is the main determinant of caveolae and a central component of several signal transduction pathways. Furthermore, CD4 downregulation and modulation of the expression of alternate and co-receptors as well as pathways associated with viral integration into the genome were also observed in these cells. Putatively, these modifications interfere with re-infection and the early replication cycle and inhibit cell death provoked by syncytia formation and bystander apoptosis. Conclusions: Thus, by using the novel approach for network analysis, ICF, we predict that in the T cell line chronically infected with SIV, cellular processes that are known to be crucial for early phases of HIV/SIV replication are altered and cellular responses that result in cell death are modulated. These modifications presumably contribute to cell survival despite chronic infection.

Original languageEnglish
Article number152
JournalVirology Journal
Volume11
Issue number1
DOIs
Publication statusPublished - 27 Aug 2014
Externally publishedYes

Keywords

  • Caveolin-1
  • CD4
  • Chronic SIV/HIV infection
  • Human T cell line
  • Key gene prediction
  • Network analysis
  • Systems biology
  • Transcriptome
  • Virus-host-interaction

Fingerprint

Dive into the research topics of 'Identification of molecular sub-networks associated with cell survival in a chronically SIVmac-infected human CD4+ T cell line'. Together they form a unique fingerprint.

Cite this