K v 1.3-induced hyperpolarization is required for efficient Kaposi’s sarcoma–associated herpesvirus lytic replication

Abstract

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 v 1.3 in B cells enhanced KSHV lytic replication. The KSHV replication and transcription activator (RTA) protein increased the abundance of K v 1.3 and led to enhanced K + channel activity and hyperpolarization of the B cell membrane. Enhanced K v 1.3 activity promoted intracellular Ca 2+ influx, leading to the Ca 2+ -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 v 1.3 blockers or silencing. These findings highlight K v 1.3 as a druggable host factor that is key to the successful completion of KSHV lytic replication.