TY - JOUR
T1 - Kaposi’s sarcoma herpesvirus latency-associated nuclear antigen broadly regulates viral gene expression and is essential for lytic infection
AU - Li, Shijun
AU - Wang, Mengbo
AU - Sciver, Nicholas Van
AU - Szymula, Agnieszka
AU - Tumuluri, Vinayak Sadasivam
AU - George, Athira
AU - Ramachandran, Akshaya
AU - Raina, Komal
AU - Costa, Catarina N.
AU - Zhao, Bo
AU - Kazemian, Majid
AU - Simas, J. Pedro
AU - Kaye, Kenneth M.
N1 - Publisher Copyright:
Copyright: © 2024 Li et al.
PY - 2024/1/17
Y1 - 2024/1/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85182774163&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1011907
DO - 10.1371/journal.ppat.1011907
M3 - Article
C2 - 38232124
AN - SCOPUS:85182774163
SN - 1553-7366
VL - 20
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 1
M1 - e1011907
ER -