# CHIP/STUB1 suppresses the transcription and latent reactivation of HIV-1 via the TRAF6-NF-κB-HIV-LTR axis

## TL;DR

This study shows that the protein CHIP suppresses HIV-1 replication and latency by inhibiting the TRAF6-NF-κB signaling pathway, offering a potential new target for HIV treatment.

## Contribution

The study reveals a novel mechanism by which CHIP inhibits HIV-1 transcription and latency through TRAF6 degradation.

## Key findings

- CHIP suppresses HIV-1 LTR transcription by degrading TRAF6 via the ubiquitin–proteasome pathway.
- The TPR domain of CHIP independently facilitates TRAF6 degradation via K48-linked polyubiquitination.
- CHIP inhibits HIV-1 latency reactivation in multiple models by repressing NF-κB signaling.

## Abstract

HIV-1 replication, transcription and latency are correlated with the activation of NF-κB signaling. C-terminus of Hsc70-interacting protein (CHIP or STUB1), a cellular E3 ligase, has been reported to inhibit Tat-mediated HIV-1 LTR promoter activity by degrading Tat. In this study, we demonstrated that CHIP modulates HIV infection by limiting viral transcription through an uncharacterized mechanism involving the negative regulation of TRAF6-NF-κB signaling. Mechanistically, CHIP targets the NF-κB signaling transducer TRAF6 but not TRAF2 or p65 for degradation via the ubiquitin–proteasome pathway, leading to the inhibition of TRAF6-mediated NF-κB signaling, which in turn suppresses NF-κB-dependent HIV-1 LTR transcription. Notably, in addition to the U-box domain, which is well known for protein degradation, the TPR domain of CHIP plays an independent role in facilitating the proteasome-mediated degradation of TRAF6 via K48-linked polyubiquitination. Furthermore, CHIP plays an inhibitory role in the reactivation of HIV-1 latency in various models, in concert with its repressive effect on the NF-κB pathway. Thus, these findings reveal that CHIP is a novel repressor of NF-κB-driven HIV-1 promoter transactivation, providing new insights into the molecular mechanisms by which upstream NF-κB signaling influences HIV-1 replication, transcription and latency.

The constant latency of human immunodeficiency virus type 1 (HIV-1) is the main barrier to eradicating the virus from infected individuals by current therapeutics. Host factors involved in HIV LTR promoter transcription regulation through NF-κB signaling are far from fully understood. In this manuscript, we demonstrated that the C-terminus of Hsc70-interacting protein (CHIP or STUB1) suppresses HIV-1 postintegration transcription and facilitates the maintenance of viral latency via the TRAF6-NF-κB-HIV-LTR axis. We found that CHIP targets the NF-κB signaling transducer TRAF6 for proteasome-mediated degradation via K48-linked polyubiquitination, leading to the inhibition of TRAF6-mediated NF-κB signaling and the suppression of NF-κB-dependent HIV-1 LTR-driven transcription. We demonstrated that the TPR domain together with the U-box domain of CHIP play critical roles in facilitating the proteasome-mediated degradation of TRAF6. Overall, these results show that CHIP influences HIV expression and latency. CHIP may be a useful new target for reactivating HIV gene expression in people with HIV.