Novel pathways of HIV latency reactivation revealed by integrated analysis of transcriptome and target profile of bryostatin

The reactivation of HIV latency cell will be necessary to curing HIV infection. Although many latency-reversal agents (LRAs) have proven effective to reactivate the latency cell, there is a lack of any systematic analysis of the molecular targets of these LRAs and related pathways in the context of transcriptome. In this study, we performed an integrated analysis of the target profile of bryostatin and transcriptome of the reactivated CD4⁺ T cells after exposing to bryostatin. The result showed a distinct gene expression profile between latency cells and bryostatin reactivated cells. We found bryostatin can target multiple types of protein other than only protein kinase C. Functional network analysis of the target profile and differential expressed genes suggested that bryostatin may activate a few novel pathways such as pyrimidine metabolism, purine metabolism and p53 signaling pathway, besides commonly known pathways DNA replication, cell cycle and so on. The results suggest that bryostatin may reactivate the HIV-latent cells through up-regulation of pyrimidine and purine metabolism or through starting the cell-cycle arrest and apoptosis induced by up-regulation of p53 signaling pathway. Our study provides some novel insights into the role of bryostatin and its affected pathways in controlling HIV latency and reactivation.