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

• Published in: PLoS pathogens 2024-01, Vol.20 (1), p.e1011907-e1011907
• Main Authors: Li, Shijun, Wang, Mengbo, Van Sciver, Nicholas, Szymula, Agnieszka, Tumuluri, Vinayak Sadasivam, George, Athira, Ramachandran, Akshaya, Raina, Komal, Costa, Catarina N, Zhao, Bo, Kazemian, Majid, Simas, J Pedro, Kaye, Kenneth M
• Format: Article
• Language: English
• Subjects: Analysis; Antigens; Antigens, Viral - genetics; Antigens, Viral - metabolism; Biology and Life Sciences; Care and treatment; Chromosomes; Complications and side effects; Diagnosis; Gene Expression; Gene Expression Regulation, Viral; Genes; Genetic aspects; Genomes; Genomics; Health aspects; Herpes; Herpes viruses; Herpesvirus 8, Human - physiology; Herpesvirus diseases; Humans; Infection; Infections; Kaposi's sarcoma; Latency; Latency-associated nuclear antigen; Latent infection; Malignancy; Medicine and Health Sciences; Microscopy; Nuclear Proteins; Permissive cells; Proteins; Research and analysis methods; Sarcoma; Sarcoma, Kaposi; Scientific equipment and supplies industry; Testing; Viral infections; Virus Latency - genetics; Virus Replication
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011907

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.