Quantifying the dynamics of Kaposi’s sarcoma-associated herpesvirus persistence

MadeleineGastonguay

Johns Hopkins University

"Quantifying the dynamics of Kaposi’s sarcoma-associated herpesvirus persistence"

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a causative agent of several lymphoproliferative diseases, particularly in immunocompromised individuals. These malignancies originate from latently infected B cells, where KSHV persists as extrachromosomal episomes. While the viral protein LANA is essential for viral maintenance during latency, the mechanisms enabling lifelong persistence remain unclear. To quantify episome dynamics, we developed a mathematical model of latent KSHV replication and segregation during cell division, and a statistical framework to infer viral dynamics from fluorescent microscopy images. We built a Gibbs sampler to extract episome counts from imperfectly resolved images of pre- and post-division cells. Using these counts, we estimate the efficiency of replication and segregation, propagating imaging uncertainty into our parameter estimates. Our framework, validated on synthetic data, provided similar estimates of replication efficiency (78%, 95% CI [53%, 90%]) and segregation efficiency (91% [78%, 100%]) when applied to fixed and live images of cells transfected with either full-length KSHV or a minimal plasmid capable of episome maintenance. Simulations of a dividing cell population showed that imperfect replication and segregation preclude decades-long persistence without the assistance of additional mechanisms such as cell-survival benefits to infection or occasional lytic replication. We also modeled KSHV-dependent malignancies to evaluate episome replication and segregation as targets to control tumor growth. Simulations revealed that reducing replication effectively disrupts tumor growth, with the required reduction dependent on cell division kinetics. Our results suggest that KSHV employs a partitioning mechanism, as opposed to random segregation, though replication and segregation are imperfect. Furthermore, targeting episome replication may offer a viable strategy to reduce tumor burden in KSHV-associated malignancies.
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