POLE3 is a transcriptional repressor of unintegrated linear HIV-1 DNA required for efficient virus integration and escape from innate immune sensing.

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Abstract Unintegrated retroviral DNA are transcriptionally silent by mechanisms involving host chromatin silencing factors1–3. Here, we applied the proteomics of isolated chromatin segments approach (PICh)4 to reveal the proteomic of the linear unintegrated HIV-1 DNA (uniHIV-1 DNA) with the aim of identifying viral and host factors involved in its chromatin-mediated silencing 1–3 . Gene invalidation using siRNAs targeting the 456 candidates selected for their specific binding to HIV-1 DNA identified 46 factors as potential repressors of uniHIV-1 DNA. Knockdown (KD) and Knockout (KO) experiments revealed POLE3, the non-essential subunit of the polymerase epsilon (POLE), as a transcriptional repressor of the linear uniHIV-1 DNA in different cell types including primary CD4 T cells. POLE3 functions by maintaining the uniHIV-1 DNA in chromatin repressed state, preventing RNAPII recruitment to the viral LTR. We found that POLE3 and the recently identified host factors silencing uniHIV-1 DNA (CAF1 and SMC5/SMC6/SLF2) show specificity towards different forms of uniHIV-1 DNA. Unexpectedly, loss of POLE3 impaired HIV-1 replication, suggesting that derepression of unintegrated linear HIV-1 DNA is detrimental to the virus. Loss of POLE3 reduces HIV-1 integration efficiency without affecting viral DNA synthesis. Remarkably, we found that POLE3, by maintaining a repressive chromatin structure of uniHIV-1 DNA, ensures HIV-1 escape from innate immune sensing in primary CD4 T cell.

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