Attenuated poxviruses like modified vaccinia virus Ankara (MVA) are promising vectors for
vaccines against
infectious diseases and
cancer. However, host innate immune responses interfere with the viral life cycle and also influence the immunogenicity of
vaccine vectors. Sterile alpha motif (SAM) domain and
histidine-
aspartate (HD) domain-containing
protein 1 (SAMHD1) is a
phosphohydrolase and reduces cellular deoxynucleoside
triphosphate (dNTP) concentrations, which impairs poxviral DNA replication in human dendritic cells (DCs). Human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) encode an accessory
protein called
viral protein X (Vpx) that promotes proteasomal degradation of SAMHD1, leading to a rapid increase in cellular dNTP concentrations. To study the function of SAMHD1 during MVA
infection of human DCs, the SIV vpx gene was introduced into the MVA genome (resulting in recombinant MVA-vpx).
Infection of human DCs with MVA-vpx led to
SAMHD1 protein degradation and enabled MVA-vpx to replicate its
DNA genome and to express genes controlled by late promoters. Late gene expression by MVA-vpx might improve its
vaccine vector properties; however,
type I interferon expression was unexpectedly blocked by Vpx-expressing MVA. MVA-vpx can be used as a tool to study poxvirus-host interactions and vector safety.IMPORTANCE SAMHD1 is a
phosphohydrolase and reduces cellular dNTP concentrations, which impairs poxviral DNA replication. The simian SIV accessory
protein Vpx promotes degradation of SAMHD1, leading to increased cellular dNTP concentrations. Vpx addition enables poxviral DNA replication in human dendritic cells (DCs), as well as the expression of viral late
proteins, which is normally blocked. SAMHD1 function during modified vaccinia virus Ankara (MVA)
infection of human DCs was studied with recombinant MVA-vpx expressing Vpx.
Infection of human DCs with MVA-vpx decreased
SAMHD1 protein amounts, enabling MVA DNA replication and expression of late viral genes. Unexpectedly,
type I interferon expression was blocked after MVA-vpx
infection. MVA-vpx might be a good tool to study SAMHD1 depletion during poxviral
infections and to provide insights into poxvirus-host interactions.