16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

MICROARRAY BASED STUDY OF EARLY INTERACTIONS BETWEEN HIV-1 AND A PBMC POPULATION HIGHLY ENRICHED IN CD4+ T CELLS

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0204

Imbeault M., Tremblay M.J.
Centre Hospitalier de l'Université Laval (CHUL), Centre de recherche en Infectiologie (CRI), Quebec, Canada

BACKGROUND: HIV-1 induces apoptosis in bystander CD4+ T lymphocytes, a process mediated by gp120 dependant p53 activation three days post-infection. However, early events following exposition to HIV-1 are not well characterized, especially in primary cells.

METHODS: We enriched a PBMC population for CD4+ T lymphocytes using negative magnetic beads based selection. HIV-1 infected cells and corresponding controls were harvested at 8 and 24 hours post-infection. Affymetrix microarray technology was used to identify early modulated genes in the CD4+ T lymphocytes enriched population. Infection percentages were assessed using a GFP reporter virus. Gene Ontology (GO) surrepresentation analysis identified the most affected biological processes and automated literature data mining was performed using Genomatix Bibliosphere in order to extract biological relationships between modulated genes.

RESULTS: We found that HIV-1 rapidly influence up to 489 genes at 24 hours post-infection. Contrarily to what was observed in CD4+ T lymphocytes cell lines, infection percentages are very low in primary cells (about 10 percent after 5 days and less than 1 percent after 24 hours post-infection); therefore, most of the observed transcriptional changes come from the bystander, uninfected population. Gene ontology analysis revealed that many of the modulated genes are involved in biological processes such as apoptosis, DNA repair, cellular cycle and RNA metabolism. Interestingly, it appears that p53 is overexpressed as soon as 8 hours following HIV-1 infection, a phenomenon that was not observed in cell lines. As we found out, p53 plays a central role in the early induced transcriptional response. We also identified multiple p53 related genes (GADD34, YY1 and TP53BP2) that show differential regulation following HIV-1 infection.

CONCLUSIONS: We conclude that HIV-1 rapidly influences the transcriptional profile of primary CD4+ T lymphocytes and sensitizes bystanders CD4+ T lymphocytes to apoptosis, primarily via p53 upregulation.

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2006-08-13
ThAa0204

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