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Transcriptome analysis of monocyte‐ HIV interactions

Thursday, 17 December, 2009 - 14:00
Campus: Brussels Humanities, Sciences & Engineering campus
Faculty: Science and Bio-engineering Sciences
Rafael Van den Bergh
phd defence

Macrophages, and monocytes as their less differentiated counterparts, play a fundamental yet
underexplored role during HIV infection. While monocytes and macrophages can be infected by HIV,
they do not enter apoptosis upon infection. Hence, they can act as a reservoir for the virus, from
where it can continue to replicate even during highly active antiretroviral therapy (HAART).
Furthermore, they develop a broad variety of dysfunctions, which contribute to quasi every step of
HIV pathogenesis. In this work, we have focused on transcriptome profiling as a means for the
confirmation of existing and generation of novel hypotheses concerning the molecular processes
underpinning monocyte‐HIV interactions.

In first instance, we have developed a custom transcriptome profiling tool focused on gene
expression analysis of human myeloid cells. This screening tool is capable of rapidly, sensitively and
cost‐effectively assessing the expression pattern of subset of genes with known and documented
monocyte/macrophage function in a large collection of samples. This assay was then applied to the
analysis of monocytes isolated from two populations of HIV patients: a transversal group of therapynaïve
patients in different stages of the disease, and a longitudinal group of patients followed up
during their first 9 months of HAART. A collection of genes was compiled with documented functions
in monocyte/macrophage‐associated processes known to be dysfunctional during HIV infection. Such
a collection may constitute the basis for further research into specific areas of
monocyte/macrophage dysfunction. Additionally, we were able to establish which genes were
restored by therapy to control levels and which genes were persistently dysregulated, suggestive of
an irreversible dysfunction at the level of the monocyte/macrophage, even under HAART.

One of the genes identified in our transcriptome analysis, the novel adipocytokine
visfatin/NAMPT, showed a set of interesting properties, in that it was capable of selectively inhibiting
infections by CCR5‐using strains of HIV, but not CXCR4‐using strains. These results, combined with
the association of visfatin expression with dominance of CXCR4‐using virus in the plasma, allowed us
to formulate the hypothesis that visfatin could be involved in the so‐called coreceptor switch of HIV,
which occurs in ~50% of all subtype B infected patients. The coreceptor switch, which entails the
change in preferential coreceptor usage from CCR5 to CXCR4, is frequently associated with a rapid
progression to AIDS. Visfatin shows promise as a molecular marker for this switch, and potentially
plays a driving role in its establishment.

Attachment: 
PDF icon 200912172a.pdf