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07:02
Identifying Dysregulated Genes Induced by Kaposi's Sarcoma-associated Herpesvirus (KSHV)
Published on: September 14, 2010
An alternative Kaposi's sarcoma-associated herpesvirus replication program triggered by host cell apoptosis
Alka Prasad1, Michael Lu, David M Lukac
1Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC, USA.
Journal of Virology
|February 21, 2012
Summary
Kaposi's sarcoma-associated herpesvirus (KSHV) unexpectedly replicates via an RTA-independent pathway triggered by apoptosis. This alternative pathway accelerates viral replication and produces less infectious virus, offering new insights into KSHV pathogenesis.
Area of Science:
- Virology
- Oncology
- Cellular Biology
Background:
- Kaposi's sarcoma-associated herpesvirus (KSHV) causes neoplastic diseases like Kaposi's sarcoma, PEL, and MCD.
- KSHV exhibits latent and lytic replication cycles.
- The RTA protein (ORF50) was previously thought to exclusively control the switch from latent to lytic replication.
Purpose of the Study:
- To investigate the mechanisms regulating KSHV replication.
- To determine if KSHV replication can be triggered independently of the RTA protein.
- To characterize the kinetics and infectivity of KSHV produced via alternative replication pathways.
Main Methods:
- Generated a PEL cell line with latent KSHV and an inducible dominant-negative ORF50 mutant (ORF50ΔSTAD).
- Induced apoptosis and monitored KSHV replication in the presence of ORF50ΔSTAD.
- Utilized ORF50 small interfering RNA (siRNA) and assessed caspase activity to confirm RTA independence and the role of apoptosis.
Main Results:
- Apoptosis induction triggered high-level KSHV replication even with a dominant-negative RTA present.
- KSHV replication upon apoptosis induction was confirmed to be RTA-independent and required caspase activity.
- Apoptosis-triggered replication accelerated late gene expression by 12–24 hours and yielded less infectious virions compared to RTA-dependent replication.
Conclusions:
- KSHV utilizes at least two distinct replication pathways: a conventional RTA-dependent pathway and an alternative apoptosis-triggered pathway.
- The apoptosis-triggered pathway is RTA-independent, exhibits faster kinetics, and produces less infectious virus.
- This discovery has significant implications for understanding KSHV-associated neoplasms and developing therapeutic strategies.
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