Cowpox Virus Inhibits the Transporter Associated with Antigen Processing to Evade T Cell Recognition

Abstract

SUMMARY Cowpox virus is considered ancestral to orthopoxviridae since CPXV encodes the most extensive array of putative immunomodulators that likely contribute to its wide host range including zoonotic infections in humans. Unlike vaccinia virus, CPXV prevents stimulation of CD8+ T cells and this correlated with retention of MHC-I in the endoplasmic reticulum by CPXV203. However, deletion of CPXV203 did not restore MHC-I transport or T cell stimulation. Here, we demonstrate that the type II transmembrane protein, CPXV012, additionally interferes with MHC-I/peptide complex formation by inhibiting peptide translocation by TAP. CPXV012 thus represents the first non-herpesvial TAP inhibitor. Importantly, human and mouse MHC-I transport and T cell stimulation was restored upon deletion of both CPXV012 and CPXV203 suggesting that these unrelated proteins independently mediate T cell evasion in multiple hosts. Interestingly, CPXV012 is a truncated version of a putative NK cell ligand indicating that poxviral gene fragments can encode new unexpected functions.

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

“…In contrast, it remains possible that the virus (or host cell) encodes proteins to interfere specifically with Clr/Clec2 function, perhaps through direct association and trafficking by the C-type lectin-related proteins or through virally encoded proteins that drive ubiquitination (43). Poxviruses are known to employ several strategies to block expression of host proteins that are involved in activation of the immune response (44)(45)(46), and there are indications that Clr-b might be involved in immune activation, making it a target for the virus. For example, exposure of human APCs to inactivated viruses or pathogen mimetics produces a substantial increase of LLT1, a human Clr-b homolog, which may protect APCs from NK cell attack (47).…”

Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

“…Defects in processing molecules, such as proteasome or TAP subunits, have been described as a strategy for countering the host T cell response. Indeed, viruses are able to interfere with MHC-I-viral peptide complex formation by inhibiting TAP so as to evade CTL recognition and destruction of infected cells (3)(4)(5)(6)(7)(8)(9)(10). TAP deficiencies have also been observed in a wide variety of human cancers, including cervical carcinoma (11), head and neck carcinoma (12), melanoma and gastric cancer (13)(14)(15), and are associated with tumor escape from immune system control.…”

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

“…CPXV has the largest genome in the orthopoxvirus genus (34) and contains several ORFs not found in either the VV or ECTV genome. This includes two ORFs, CPXV012 and CPXV203, that potently down-regulate the expression of MHC class I (35)(36)(37)(38). Although this might render the infected cell sensitive to NK cell-mediated lysis, CPXV also encodes another ORF, CPXV018, that binds in vitro with high affinity to the NKG2D activation receptor and blocks its recognition of ligands on target cells (39).…”