197 Naturally Occurring C-terminally Truncated Isoform of STAT5 (STAT5Δ) Is a Transcriptional Repressor of HIV-1 Expression. Characterization of the Platinum- Based STAT Inhibitor CPA-7

Abstract

Signal transducers and activator of transcription (STAT) proteins, namely STAT1 and STAT5Δ, are frequently constitutively activated in the PBMC of most of HIV-1+ individuals. We previously described that STAT5Δ is also the only STAT5 isoform detectable in the chronically HIV-1 infected promonocytic cell line U1 characterized by a constitutive state of viral latency and inducibility of virus expression by PMA or several cytokines. We have recently reported that STAT5Δ can act as inhibitor of HIV-1 transcription in GM-CSF-stimulated U1 cells and IL-2 stimulated PBMC of HIV+ individuals due to its binding to target DNA sequence in the provirus LTR causing an impaired recruitment of RNA Pol II (A. Crotti et al., Blood, 2007). GM-CSF also triggered the late activation of an ERK/AP-1 dependent pathway inducing HIV-1 expression in U1 cells. Selective inhibition of this pathway turned off, while inhibitors of STAT5 enhanced, viral expression in GM-CSF stimulated U1 cells. We are currently investigating a new platinum-based compound, termed CPA-7, reported to interfere with STAT3 in several solid tumor cell lines by inducing apoptosis. Our preliminary results demonstrate that CPA-7 increased HIV-1 expression in GM-CSF stimulated U1 cells. Further investigation will clarify the role of this compound in the context of STAT-induced HIV-1 expression and will suggest a possible therapeutic use of CPA-7 in the context of HIV reactivation from latently infected cells.