Inhibition of telomerase activity contributes to HIV‐1‐induced activation of inflammatory responses and alteration of tight junction protein expression in human brain endothelial cells

Abstract

Telomerase reverse transcriptase (TERT) is a catalytic rate‐limiting component of telomerase. Progressive telomere shortening has been observed to contribute to cell senescence. To determine whether TERT activity can contribute to HIV‐1 induced endothelial dysfunction, senescence of human brain endothelial cells (hCMEC/D3 cell line) was induced by inhibition of telomere activity via a siRNA directed against human TERT. These cells were then exposed to HIV‐infected Jurkat cells and evaluated for the induction of inflammatory mediators and the barrier function. Inhibition of hTERT resulted in upregulation of HIV‐1 induced mRNA and protein expressions of intercellular adhesion molecule (ICAM)‐1 and vascular cell adhesion molecule (VCAM‐1). In contrast, hTERT deficiency potentiated HIV‐induced downregulation of expression of tight junction proteins such as zonula occludens (ZO)‐1, ZO‐2, and claudin‐1. These alterations were associated with elevated transendothelial migration of HIV‐infected monocytes. The present findings indicate that cell senescence induced by inhibition of hTERT in brain endothelial cells may contribute to HIV‐1 induced endothelial dysfunction of brain blood barrier. Supported by MH63022, MH072567, and NS39254.