THE HIV-1 SILENCER BCL11B/CTIP2 REGULATES THE TLR3-MEDIATED CELLULAR RESPONSE TO VIRAL INFECTIONS

Abstract HIV-1 latency remains a major barrier to viral eradication. The persistence of the latently infected reservoirs results from multifactorial mechanisms controlling gene transcription and cellular responses to viral reactivation. The transcriptional repressor BCL11B/CTIP2 is known to promote the establishment and persistence of the latently infected reservoirs. However, its contribution to the cellular response to viral infection has not been investigated before. Together with HEXIM1, paraspeckles contribute to cellular innate sensing of viral infections and to the production of type I interferons. Paraspeckles are nuclear membrane-less organelles composed of proteins, including SFPQ/PSF and NONO, wrapped around the long non-coding RNA NEAT1. Here, we show that HIV-1 infection promotes a TLR3-mediated CTIP2 overexpression delayed from a transitory NEAT1 overexpression, paraspeckles formation and type I IFN production. In response to this interferon production, CTIP2 is recruited to the NEAT1 promotor together with HEXIM1 and repressive histone marks to inhibit NEAT1 gene expression. The resulting depletion of the paraspeckles abrogated INF production, dampening TLR3 signalling and reinforcing HIV-1 latency. Our results demonstrate CTIP2 as a dual-function regulator that silences HIV-1 transcription and restricts antiviral innate immune response as part of a negative feedback loop limiting the interferon response to viral infection. Competing Interest Statement The authors have declared no competing interest.