Kaposi's sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection.

Kaposi's sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA also maintains latency by antagonizing expression and function of the KSHV lytic switch protein, RTA. Here, we find LANA null KSHV is not capable of lytic replication, indicating a requirement for LANA. While LANA promoted both lytic and latent gene expression in cells partially permissive for lytic infection, it repressed expression in non-permissive cells. Importantly, forced RTA expression in non-permissive cells led to induction of lytic infection and LANA switched to promote, rather than repress, most lytic viral gene expression. When basal viral gene expression levels were high, LANA promoted expression, but repressed expression at low basal levels unless RTA expression was forcibly induced. LANA's effects were broad, but virus gene specific, extending to an engineered, recombinant viral GFP under control of host EF1α promoter, but not to host EF1α. Together, these results demonstrate that, in addition to its essential role in genome maintenance, LANA broadly regulates viral gene expression, and is required for high levels of lytic gene expression during lytic infection. Strategies that target LANA are expected to abolish KSHV infection. Author summary: Kaposi's sarcoma herpesvirus (KSHV) is a leading cause of cancer in those with AIDS and current therapies are limited. Like other herpesviruses, KSHV infects cells in two forms, causing latent or lytic infection. KSHV latency-associated nuclear antigen (LANA) is essential for viral latency since it maintains the extrachromosomal viral genome in dividing cells. LANA also maintains latency by antagonizing the KSHV lytic switch protein, RTA, which is capable of triggering lytic replication. Here, we find KSHV lacking LANA is incapable of lytic infection, indicating LANA is required for lytic replication. Further, LANA can have dual effects on viral gene expression. In cells partially permissive for lytic KSHV infection, LANA promoted viral gene expression, but repressed expression in non-permissive cells. Forced RTA expression in non-permissive cells led to LANA switching to promote, rather than repress, most lytic viral gene expression. We found when basal viral gene expression levels were high, LANA promoted expression, while LANA repressed expression at low basal levels. These results show that, in addition to its essential role in genome maintenance, LANA is required for the elevated levels of lytic gene expression that occur during lytic infection. Future approaches that inactivate LANA are expected to abolish KSHV infection. [ABSTRACT FROM AUTHOR]