One way in which viruses escape the host immune response and establish a persistent infection is by impairing T-cell activation. New research now shows that T-cell lymphotropic herpesvirus saimiri (HVS) — which induces T-cell lymphomas in infected primates — is able to achieve this goal by preventing activation of the protein tyrosine kinase ZAP70 (ζ-chain-associated protein kinase of 70 kDa).

The HVS tyrosine-kinase-interacting protein (Tip) has been shown to interact with LCK and disrupt signalling through the T-cell receptor (TCR). So, to investigate the molecular mechanism of this effect, Cho et al. overexpressed wild-type Tip and various Tip mutants in purified human peripheral-blood T cells and the Jurkat T-cell line. Overexpression of Tip markedly diminished the production of interleukin-2 and inhibited the rise in intracellular calcium concentration induced by TCR triggering, and this effect was dependent on its interaction with LCK.

LCK is known to phosphorylate tyrosine residues in the CD3 subunits of the TCR, leading to the recruitment and activation of ZAP70 through its phosphorylation. In the presence of Tip, tyrosine phosphorylation of CD3ζ and recruitment of ZAP70 occurred normally, but phosphorylation of ZAP70 was not observed. Further evidence that Tip inhibits ZAP70 activation was provided by the observation that phosphorylation of ZAP70 substrates (linker for activation of T cells (LAT) and phospholipase C-γ1) was not detected in the presence of Tip. In addition, Tip expression inhibited immunological-synapse formation, an event downstream of TCR signalling that is crucial for T-cell activation.

This study shows that HVS uses Tip to inhibit the activation of ZAP70, thereby disrupting the subsequent T-cell signalling cascades required for T-cell activation. The authors suggest that this enables HVS to escape the host immune response and establish a persistent infection.