132 A Novel Pathway of Proviral HIV-1 Latency Regulated by Aminoacid Starvation and HDAC4

An intrinsic property of all retroviruses is their capacity to establish a state of latent infection in addition to active viral replication. Both genetic and epigenetic factors contribute to silence the integrated provirus and are nowadays targets of experimental approaches aiming at reactivating virus expression in order to kill the infected cells either by immune-mediated mechanisms (such as CTL) or by pharmacological agents. We have recently uncovered an unsuspected pathway triggered by essential aminoacid starvation and involving the downregulation of HDAC4, a class II HDAC, leading to a significant uprising of latent HIV-1 infection in chronically infected cell lines, such as ACH-2 cells, expressing this enzyme, but not in similar cell lines, such as U1, negative for HDAC4 expression. Both pharmacological targeting of HDAC4 and siRNA-mediated downregulation of its expression gave the same result. A similar phenomenon was observed for heterologous transgenes, driven by different promoters, introduced for gene therapy purposes, but not for their endogenous counterparts. This observation suggests that the mTOR-independent pathway triggered by aminoacid starvation and involving HDAC4 modulation represents or contributes to an intracellular response to foreign nucleic acids (I. Palmisano et al., PNASPlus 2012). More recent results with a broader variety of HIV-1 latency models will be discussed.