Nucleoporin NUP98 suppresses the basal HIV-1 gene expression through its N-terminal domain

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Abstract Background: Nucleoporins (NUPs) are cellular effectors of HIV-1 replication that support nucleocytoplasmic trafficking of viral components, and non-canonically promote viral DNA integration into the host genome and proviral DNA transcription. However, some of the NUPs were also shown to aid the host restriction factor MX2 to inhibit the replication of HIV-1, indicating both pro- and anti-viral role for NUPs towards HIV-1 replication. Results: Here, we examined the expression of NUPs such as NUP98, NUP62, NUP155, NUP133, NUP107 and NUP85 during HIV-1 infection, and observed that the expression of NUP98 was downregulated. However, its cellular localization remained unchanged. Over-expression, supplemented with knockdown studies indicated that NUP98 negatively affected HIV-1 LTR promoter activity. This negative effect on promoter activity was independent of HIV-1 Tat suggesting that NUP98 prevents the basal viral gene expression from HIV-1 LTR promoter. Further we demonstrated that NUP98 associated with HIV-1 LTR promoter, and that NUP98-mediated perturbation in viral gene transcription was independent of host factors, HEXIM1 and NF-kB. The attenuation of HIV-1 LTR-driven transcription was predominantly contributed by the N-terminal domain of NUP98. Conclusions: Our experimental evidence for the first time demonstrates that NUP98 associates with HIV-1 LTR and suppresses the viral gene transcription. HIV-1, attempting to downregulate NUP98, supports the concepts of evolutionary conflicts between viruses and host anti-viral factors.

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