PA28γ is a novel corepressor of HTLV-1 replication and controls viral latency

The establishment of a latent reservoir by human tumor viruses is a vital step in initiating cellular transformation and represents a major shortcoming to current therapeutic strategies and the ability to eradicate virus-infected cells. Human T-cell leukemia virus type 1 (HTLV-1) establishes a lifelong infection and is linked to adult T-cell leukemia lymphoma (ATLL). Here, we demonstrate that HTLV-1 p30 recruits the cellular proteasome activator PA28 gamma onto the viral tax/rex mRNA to prevent its nuclear export and suppress virus replication. Interaction of p30 with a PA28 gamma retaining fully functional proteasome activity is required for p30's ability to repress HTLV-1. Consistently, HTLV-1 molecular clones replicate better and produce more virus particles in PA28 gamma-deficient cells. These results define a unique and novel role for the cellular factor PA28 gamma in the control of nuclear RNA trafficking and HTLV-1-induced latency. Importantly, knockdown of PA28 gamma expression in ATLL cells latently infected with HTLV-1 reactivates expression of viral tax/rex RNA and the Tax protein. Because Tax is the most immunogenic viral antigen and triggers strong CTL responses, our results suggest that PA28 gamma-targeted therapy may reactivate virus expression from latently infected cells and allow their eradication from the host. (Blood. 2013;121(5):791-800)