Importin KPNA2 confers HIV-1 pre-integration complex nuclear import by interacting with the capsid protein

For human immunodeficiency virus 1 (HIV-1) to infect non-dividing cells, pre-integration complex (PIC) must be transported into the nucleus within the replication cycle. We previously reported that the karyopherin β1 (KPNB1)-nucleoporin Pom121 pathway, related to the downstream process of PIC nuclear import, mediates efficient HIV-1 PIC nuclear import. Further, our earlier RNA transcriptome sequencing revealed that karyopherin α2 (KPNA2) was among the differentially expressed importin family members during monocyte to macrophage differentiation. Although PIC transport into the nucleus in HIV-1 has been widely studied, much remains to be understood about it. In this study, we confirmed our previous RNA sequencing results and found that HIV-1 replication was significantly lower in 293T cells with siRNA-mediated KPNA2 knockdown and higher in KPNA2-upregulated cells. Quantitative PCR indicated that viral replication was impaired during cDNA nuclear import. The N-terminal of the capsid protein p24 interacted with KPNA2, and KPNB1 participated in KPNA2-mediated PIC nuclear import. Disruption of the capsid-KPNA2 binding by overexpression of full-length p24 or p24 N-terminal impaired the PIC nuclear import. These results indicate that KPNA2 is an important upstream adaptor of the KPNB1-Pom121 axis, thereby mediating HIV-1 PIC nuclear transportation. KPNA2 is thus a potential target for HIV-1 antiviral treatment.