HIV-2 Vpx neutralizes host restriction factor SAMHD1 to promote viral pathogenesis

Abstract

SAMHD1, a human host factor found in myeloid cells which restricts HIV-1 replication. It depletes the dNTPs pool for viral cDNA syntheses, thus preventing the viral replication in the cells. The viral accessory protein, Vpx, exists only in SIVmac/HIV-2 particles. Vpx in SIVmac can induce proteosomal degradation of SAMHD1, which then leads to a decrease in the cytoplasmic dNTP pool. The protein–protein interaction between Vpx and SAMHD1 and its consequences are still unclear. Methods: In this study, we cloned, for the first time, Vpx gene from a HIV-2 infected patient and found up to 30% sequence variation compared to known HIV-2 strains. We then analyzed the role of SAMHD1 protein expression in transfected THP-1 and U937 cells by transfecting with the Vpx gene derived from SIVmac, HIV-2 from the NIH sample as well as HIV-2 from a Saudi patient. We found that Vpx gene expression led to reduced levels of intracellular SAMHD1. When the supernatants of the transfected cell lines were examined for secreted cytokines, chemokines and growth factors, Vpx expression seemed to be suppressive of pro-inflammatory response, and skewed the immune response towards an anti-inflammatory response. These results suggest that Vpx can act at two levels: clearance of intracellular restriction factor and suppression of cytokine storm: both aimed at long-term latency and host–pathogen stand-off, suggesting that Vpx is likely to be a potential therapeutic target.

Transcriptomic analysis reveals key pathways influenced by HIV-2 Vpx

“…It was previously shown that HIV-1 Vpr can induce IL-6 production in monocyte-derived macrophages (MDMs) [54]. When we assayed for the level of cytokines in the medium of transfected cells, we found that Vpx resulted in the increase of proin ammatory cytokines (IL-6 and IL-1β), in addition to TGFβ, which is in agreement with other's ndings [55], where level of secreted IL-6 and IL-1β were signi cantly increased in SIV and HIV-2 infected cells. This nding supports the role of HIV-2 Vpx in modulating the immune system.…”

Interferon-inducible SAMHD1 restricts viral replication through downregulation of lipid synthesis

“…We note that SAMHD1 moderately inhibits HCV or JEV compared with HIV or other DNA viruses. One possibility is that these viruses evolved a partial resistance to SAMHD1 during a long evolutionary process (26). The other possibility is that some other host factors induced by type1 IFN, such as CypA, assist in the formation of HCV replicase complex or guard HIV nucleic acids from cytosolic sensors, which counters the inhibition of SAMHD1 (27).…”

E3 Ubiquitin Ligases in Gammaherpesviruses and HIV: A Review of Virus Adaptation and Exploitation

“…Reverse transcription is an essential step in the lentiviral lifecycle and SAMHD1 effectively inhibits RT and viral replication [ 220 ]. Vpx, encoded by HIV-2 and some lineages of SIV, counteracts the activity of SAMHD1 by targeting the restriction factor for proteasomal degradation [ 175 , 176 , 215 , 221 ]. Vpx and SIV Vpr assemble with DCAF1 (also known as VPRBP) a substrate receptor for Cullin 4 CRL (Cullin Ring ubiquitin ligase) and target SAMHD1 for degradation, allowing for productive infection to occur [ 175 , 176 , 177 ].…”