K_v1.3-induced hyperpolarization is required for efficient Kaposi's sarcoma-associated herpesvirus lytic replication

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus that is linked directly to the development of Kaposi's sarcoma. KSHV establishes a latent infection in B cells, which can be reactivated to initiate lytic replication, producing infectious virions. Using pharmacological and genetic silencing approaches, we showed that the voltage-gated K⁺ channel K_v1.3 in B cells enhanced KSHV lytic replication. The KSHV replication and transcription activator (RTA) protein increased the abundance of K_v1.3 and led to enhanced K⁺ channel activity and hyperpolarization of the B cell membrane. Enhanced K_v1.3 activity promoted intracellular Ca²⁺ influx, leading to the Ca²⁺-driven nuclear localization of KSHV RTA and host nuclear factor of activated T cells (NFAT) proteins and subsequently increased the expression of NFAT1 target genes. KSHV lytic replication and infectious virion production were inhibited by K_v1.3 blockers or silencing. These findings highlight K_v1.3 as a druggable host factor that is key to the successful completion of KSHV lytic replication.