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HIV MODULATES HOST GENE EXPRESSION IN MACROPHAGES AFTER IFN ALPHA2 TREATMENT
M Sirois1, L Robitaille1, M Shah1, CH Woelk2, J Corbeil1
1Québec, QC; 2San Diego, CA, USA
Objective: Innate immunity products may be beneficial to diminish the pathogenicity of infection and useful in its control. Our aim is to uncover downstream effectors of the IFN response that inhibit HIV infection.
Methods: We measured the early transcriptional responses to HIV-1 BaL infection with multiple time points (in the first 24 hrs) in primary macrophages pre-treated 18 hrs with IFN alpha(alpha)2 using high-density oligonucleotide microarrays. Three independent cell donors were tested for microarray analysis and for subsequent validation using quantitative RT-PCR. For every microarray experiment we used a ranking methodology to extract differentially expressed genes. Functional and Gene Ontology analysis then followed to determine significant functionalities associated with HIV infection after IFNalpha2 treatment of the cells.
Results: We analyzed genes that showed a significant difference in their regulation when IFNalpha2 pre-treated macrophages were infected or not with HIV. Several of those genes were associated with transcription (p=4.2E-6) and transcription regulation (p=6.0E-6). Specifically, ISGF3G, NR4A2 and NR4A3 are transcription factors up-regulated when IFNalpha2 pre-treated macrophages are inoculated with HIV compared to IFNalpha2 pre-treated macrophages without HIV exposure. Moreover, ZCCHC11 and VISA are up-regulated in IFNalpha2 pre-treated macrophages compared to untreated macrophages. ZCCHC11 is a negative regulator of one of the principal transcription factors of HIV; NFkB. VISA is involved in both virus-triggered TLR3-independent and TLR3-mediated antiviral interferon signalling. Moreover, these genes were down-regulated when the IFNalpha2 pre-treated macrophages were infected by HIV.
Conclusions: Our data revealed that HIV modulates a number of genes with transcription and transcription regulation functions in the first 24 hours post-infection. Regulation of gene expression by HIV after IFNalpha2 pre-treatment of macrophages such as ISGF3G, NR4A2, NR4A3, ZCCHC11 and VISA suggests an important role of these genes in host defense and/or HIV infection and replication.