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Differential Expression of Genes Associated with Apoptosis Predicts CD4 Decline after Interruption of ART in ACTG A5170
Maryanne Vahey*1, Z Wang2, Z Su3, A Krambrink3, D Skiest4, and D Margolis5
1Walter Reed Army Inst of Res, Washington, DC, US; 2Henry M Jackson Fndn, Rockville, MD, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Baystate Med Ctr, Springfield, MA, US; and 5Univ of North Carolina at Chapel Hill, US
Background: Patterns of expressed genes in
peripheral blood mononuclear cells (PBMC) of seropositive persons electing to
stop ART in the AIDS Clinical Trials Group Study A5170, were scrutinized to
identify markers capable of predicting significant CD4+ T cell
depletion after treatment interruption.
Methods: We matched 24 patients in A5170 whose CD4+
decline little after ART treatment interruption (mean decline 123 CD4+
cells at week 24) by nadir CD4+ cell count, with 24 patients who
suffered at least a 50% greater decline in CD4+ T cells after
treatment interruption (mean decline 401 cells at week 24). Peripheral blood
mononuclear cell (PBMC) gene expression was assessed at time of treatment
interruption and at 24 weeks. Significance Analysis of Microarrays identified
differential expression from Affymetrix genechip data. Prediction Analysis of
Microarrays identified genes corresponding with differential disease
progression. Gene Set Enrichment Analysis identified sets of genes associated
with progression at treatment interruption.
Results: Differential gene expression by week 24 was
greater in the CD4+ depletion group, with up-regulation of 133 genes
primarily associated with viral infection, and down-regulation of 208 genes,
primarily associated with metabolism. The stable group exhibited up-regulation
of 51 genes primarily associated with viral infection and cellular defense. At
treatment interruption, a set of 53 genes primarily associated with the
regulation of the cell cycle, classified persons destined for stability or CD4+
depletion with 81% accuracy. At 24 weeks post treatment interruption a set of
176 genes primarily associated with the regulation of apoptosis and immune
response achieved 83% accurate classification. At treatment interruption, Gene
Set Enrichment Analysis identified the genes PIK3CA and RAF1 of
the Ras signaling pathway as significantly up-regulated in the stable group.
Conclusions: Up-regulation of genes in the Ras
signaling pathway, specifically associated with the down-regulation of
apoptosis, is associated with good immunologic outcome in persons stopping ART.
Gene expression patterns predictive of CD4+ T cell depletion in
seropositive patients with immune preservation on ART can be identified prior
to treatment interruption, suggesting that host response patterns affect HIV
pathogenesis, and might be clinically useful in disease management. Such
studies may also help identify host responses that might be modified as a
strategy to prevent disease progression.
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