Newly developed monoclonal antibodies for marmoset immunosuppression enable KSHV lytic replication and salivary shedding: A promising model for KSHV pathogenesis studies

Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma, a malignancy that primarily affects immunocompromised individuals, and is also linked to multiple other diseases. Progress in understanding KSHV pathogenesis and developing effective vaccines or therapies has been severely limited by the lack of a reliable in vivo model that recapitulates infection, persistence, and disease. Previous work suggested that the common marmoset (Callithrix jacchus), a small New World primate, can support KSHV infection and pathogenesis, but the reproducibility and utility of this model has not been rigorously established. Here, we sought to validate the common marmoset as a non-human primate model for KSHV studies by evaluating viral infection under both immunocompetent and immunosuppressed conditions. We first tested the use of intravenous and oral tacrolimus-based immunosuppression, confirming infection in challenged marmosets but also encountering tacrolimus dosing inconsistencies and toxicity. To overcome these limitations, we developed and validated a targeted immunosuppression approach using two novel mouse-marmoset chimeric monoclonal antibodies, anti-CD4 [TAWA] and anti-CD8 [OCHO], to selectively deplete T cell subsets. Altogether, we demonstrated across four independent experiments that KSHV can establish systemic infection in both immunocompetent and immunosuppressed conditions marmosets, evidenced by viremia in peripheral blood mononuclear cells, detectable seroconversion, and tissue persistence. The chimeric antibodies mediated efficient, subset‑specific depletion of CD4+ and CD8+ T cells and enabled a quantifiable, well‑tolerated immunosuppressive regimen. Moreover, we showed for the first time that monoclonal antibody-treated marmosets exhibit KSHV shedding in saliva and lytic replication, indicating that infection in this model is not merely latent but supports a full, human‑like replication cycle. Together these findings validate the common marmoset as a susceptible and translationally relevant non-human primate for studying KSHV infection and introduce a practical immunosuppressive tool for dissecting viral pathogenesis and immunity in vivo, providing a platform for testing vaccine and therapeutics.