Cross-regulation between herpesviruses and the TNF superfamily members

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Abstract
The attachment of herpesviruses to host cells requires many steps, including initial non-specific attachment, specific attachment to entry receptors and viral fusion with the cell membrane. Herpes simplex virus (HSV) enters cells using the gD-binding receptors herpesvirus entry mediator, nectin-1, nectin-2 and a form of heparan sulphate, as well as the gB-binding receptor paired immunoglobulin-like type 2 receptor-α. HSV can use signalling that is induced by these receptors to regulate host immune responses. The human herpesviruses express several homologues of tumour-necrosis factor (TNF) receptors, which they use to provide survival and, in some cases, transforming signals to the host cells. An important mechanism of viral clearance that is used by the host immune system involves the use of the death-domain-containing TNF receptors CD95 and TNF-related apoptosis-inducing ligand receptor (TRAILR) to induce apoptosis of infected cells. Adaptive immune responses are boosted through co-stimulatory signals from TNF receptors such as OX40, which increase the numbers of virus-specific T cells to limit viral replication. The chronic pathogen cytomegalovirus induces interferon production and lymphotoxin-β receptor activation in infected cells, which results in reduced virus production and the establishment of host–pathogen 'détente'; this allows survival of both the virus and the host cell.