Abstract
Persistent infections are subject to constant surveillance by CD8+ cytotoxic T cells (CTL). Their control should therefore depend on MHC class I-restricted epitope presentation. Many epitopes are described for γ-herpesviruses and form a basis for prospective immunotherapies and vaccines. However the quantitative requirements of in vivo immune control for epitope presentation and recognition remain poorly defined. We used Murid Herpesvirus-4 (MuHV-4) to determine for a latently expressed viral epitope how MHC class-I binding and CTL functional avidity impact on host colonization. Tracking MuHV-4 recombinants that differed only in epitope presentation, we found little latitude for sub-optimal MHC class I binding before immune control failed. By contrast, control remained effective across a wide range of T cell functional avidities. Thus, we could define critical engagement thresholds for the in vivo immune control of virus-driven B cell proliferation.
Highlights
The gamma-herpesviruses infect .90% of humans and cause diseases including nasopharyngeal carcinoma, African Burkitt’s lymphoma and Kaposi’s Sarcoma
The proliferation of latently infected B cells and their control by CD8+ T cells are central to pathogenesis
With the well-established Murid Herpesvirus-4 infection model, we used a range of recombinant viruses to define functional thresholds for the engagement of a latently expressed viral epitope
Summary
The gamma-herpesviruses (cHVs) infect .90% of humans and cause diseases including nasopharyngeal carcinoma, African Burkitt’s lymphoma and Kaposi’s Sarcoma Their colonization of circulating memory B cells is crucial to persistence and to disease ontogeny. Immune recognition can be assayed in vitro; but while EpsteinBarr virus (EBV) latency gene products drive autonomous B cell proliferation in vitro, most in vivo infected cells are resting memory B cells that have passed though lymphoid germinal centers (GCs) [3]. MuHV-4 is more closely related to the Kaposi’s Sarcomaassociated Herpesvirus (KSHV) than to EBV [7] It shares many features of host colonization with EBV, for example it exploits lymphoid GCs to establish persistence in circulating memory B cells [8,9,10]. It can be used to reveal fundamental mechanisms of cHV/host interaction
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