Speaker
Description
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a causative agent of several lymphoproliferative diseases, particularly in immunocompromised individuals. These malignancies often originate from latently infected B cells, where KSHV persists as extrachromosomal, circularized 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 of cells in culture. First, we built a Gibbs sampler to extract episome counts from imperfectly resolved images of pre- and post-division cells. Using these counts, we jointly estimate the efficiency of episome replication and segregation, propagating imaging uncertainty into our parameter estimates.
Our framework, which was validated using synthetic data, provided similar estimates of replication efficiency (78%, 95% CI [53%, 90%]) and segregation efficiency (91%, 95% CI [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 but incapable of lytic replication. Forward simulations of viral persistence in a population of dividing cells indicated that imperfect replication and segregation alone preclude decades-long persistence without the assistance of additional mechanisms such as cell-survival benefits to infection or occasional lytic replication.
In addition, we modeled KSHV-dependent malignancies to evaluate reduction of replication or segregation as potential growth disruption strategies. Simulations of exponentially growing tumors demonstrated that reducing replication, but not segregation, could effectively disrupt tumor growth, and the requisite reduction depends on cell division kinetics.
These results suggest that KSHV persists by employing an active partitioning mechanism, as opposed to random segregation, but that both replication and segregation are imperfect. Furthermore, therapeutic strategies targeting episome replication may effectively reduce tumor burden for KSHV-associated malignancies.
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