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Equine herpesvirus 1 bridles T-lymphocytes to reach its target organs.
Journal of Virology 2019 January 17
Equine herpesvirus 1 (EHV1) replicates in the respiratory epithelium and disseminates through the body via a cell-associated viremia in leukocytes, despite the presence of neutralizing antibodies. 'Hijacked' leukocytes, previously identified as monocytic cells and T-lymphocytes, transmit EHV1 to endothelial cells of the endometrium or central nervous system, causing reproductive (abortigenic variants) or neurological disorders (neurological variants). Here, we questioned the potential route of EHV1 infection of T-lymphocytes, and how EHV1 misuses T-lymphocytes as a vehicle to reach the endothelium of the target organs, in the absence or presence of the immune surveillance. Viral replication was evaluated in activated/quiescent primary T-lymphocytes, and demonstrated increased infection of activated versus quiescent, CD4+ versus CD8+ , and blood- versus lymph nodal-derived T-cells. Moreover, primarily infected respiratory epithelial cells and circulating monocytic cells efficiently transferred virions to T-lymphocytes in the presence of neutralizing antibodies. Albeit the early expression of all classes of viral proteins, the expression of viral glycoproteins on the T-cell surface was restricted. In addition, the release of viral progeny was hampered, resulting in the accumulation of viral nucleocapsids in the T-cell nucleus. During contact of infected T-lymphocytes with endothelial cells, (a) late viral protein(s) orchestrate(s) T-cell polarization and synapse formation, followed by anterograde dynein-mediated transport and transfer of viral progeny to the engaged cell. This represents a sophisticated, but efficient immune evasion strategy to allow transfer of progeny virus from T-lymphocytes towards adjacent target-cells. These results demonstrate that T-lymphocytes are susceptible for EHV1 infection and that cell-cell contact transmits infectious virus to and from T-lymphocytes. Importance Equine herpesvirus 1 (EHV1) is an ancestral alphaherpesvirus related to herpes simplex virus 1, causing respiratory, reproductive and neurological disorders in Equidae EHV1 is indisputably a master in exploiting leukocytes to reach its target organs, accordingly evading the host-immunity. However, the role of T-lymphocytes in cell-associated viremia remains poorly understood. Here, we show that activated T-lymphocytes efficiently become infected and support viral replication, despite the presence of the protective immunity. We demonstrated a restricted expression of viral proteins on the cell-surface of infected T-cells, preventing immune-recognition. In addition, we indicated a hampered progeny release, resulting in the accumulation of nucleocapsids in the T-cell nucleus. Upon engagement with target endothelium, late viral proteins orchestrate a viral synapse formation, and viral transfer to the contact cell. Our findings have significant implications to understand the EHV1 pathogenesis, which is essential to develop innovative therapies, to prevent the devastating clinical symptoms.
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