## 3 Discussion
### Acute HCV Infection Reprograms Gene Transcription of Infected Cells  
Many genes regulating transcription, representing approximately 20% of all genes differentially expressed at 72 h, showed major changes in expression during acute HCV infection. Although changes in interferon stimulated and other genes during HCV infection, activated initially via PAMP (pathogen associated molecular patterns) pathways such as RIG-I and Toll-like receptors, have been well described during HCV infection this study identifies additional gene networks that are stimulated or inhibited during acute infection. This included a dramatic 10-20 fold increase in _KLF4_ and _ANKRD1_ mRNA and a 4-fold increase in _AKNA_, mRNA indicating that the gene networks they regulate undergo major changes during acute HCV infection. A number of members of the Sp1-like/KLF family of transcription factors (_SP1_, _SP5_, _KLF10_, _KLF11_, _KLF13_, _KLF15_, _KLF16_, _KLF3_, _KLF6_, _KLF9_) were significantly upregulated during acute HCV infection. They regulate the biological processes of cell growth and morphogenesis [37]. _KLF4_ was previously shown to play a crucial role in early development by regulating cell differentiation, tumor suppression, and steam cells [37, 38]. Although changes in _KLF4_ expression has not been reported during acute HCV infection, it has been found to be upregulated in macrophages infected with Sendai virus, bronchial epithelial cells infected with RSV, and in endothelial cells exposed to Candida albicans blastospores [39, 40, 41]. _AKNA_ is predominantly expressed by lymphoid tissues and encodes a protein that binds to DNA by a conserved nine amino acid domain called AT-hook, which has been implicated in regulating gene transcription by altering chromatin structure. Studies have provided evidence that _AKNA_ plays a critical role in regulating immune responses by activating the expression of the CD40 receptor and its ligand CD40L/CD154, two lymphocyte cell surface molecules critical for antigen-dependent-B-cell development [42]. Recent studies showed that _AKNA_ is a major modulator of the intensity of _in vivo_ inflammatory responses [23]. Knocking out _AKNA_ sensitizes mice to pathogen-induced inflammation and caused sudden neonatal death due to systemic inflammation, especially in the lung, induced by inflammatory cytokines (interferon-1\(\beta\), interferon-1\(\gamma\)) and proteins (neutrophilic granule protein, cathelin-related antimicrobial peptide) [23]. _AKNA_ has not been previously reported to be differentially regulated during viral infections. Our observation suggests that the _AKNA_ regulated gene network suppresses the innate response during acute HCV infection and deserves follow up studies. In addition to genes regulating transcriptional and translational processes, genes involved in RNA catabolism, both promoting (such as _UPF1_, _UPF3B_ and _SMG1_) and inhibiting RNA degradation (_RNH_, _GSTP1_ and _TNKS1 BP_) were significantly upregulated during acute HCV infection. To establish and maintain infection, RNA viruses must escape the host cell RNA decay machinery [43]. Some of the genes showing significant increases in mRNA during acute HCV infection (such as _HuR_, _PCBP2_) encode proteins that were reported as critical in protecting Sindbis and Polio viruses from host cell driven RNA decay [44, 45]. Genes involved in stabilizing cellular mRNAs, such as _PCBP4_ (poly(rC) binding protein 4) and _PCBP1_, were also significantly upregulated. Previous reports have shown _PCBP2_ is hijacked by viruses (such as polio, coxsackie and hepatitis A virus) and used to promote optimal viral translation and gene expression [46, 47, 48, 49]. In addition, _PCBP2_ and _PCBP_ isoforms are also found in stress granules and play a role in 3' end mRNA processing [48, 49]. Other differentially expressed genes that are part of RNA decay pathways that were not previously known to be alteredduring HCV infection were identified.