Host Restrictions to Viral infection: From HIV to Zika.
Type-I interferon warns cells of an intruder at the gate. It is produced by cells that cells have detected a pathogen-associated molecular patter (PAMP) recognized by various intracellular and cell-surface receptors that include toll-like receptors, MAVS and RIG-I. Cells respond to type-I interferon by rapidly inducing the transcription of interferon-stimulated genes, many of which act to counter the replication of viruses and bacteria. Many such ISGs are well-known, but there are others that remain to be discovered. We have identified several previously unknown ISGs. some are active against HIV. Others were active against Zika Virus. Once ISG we tested was viperin, a host factor that is known to act against several flaviviruses. We found that viperin was highly active against Zika. Moreover, the toll-like receptor agonist, imiquimod (R848) is an approved drug and a powerful inducer of viperin. The results suggests that TLR activation could be a means to treat viral infection that would work quite rapidly to induce an antiviral state that would reduce virus replication in an acutely infected person.
HIV-2 and SIV encode Vpx, a virion-packaged accessory protein that induces the degradation of the host restriction factor SAMHD1, allowing the virus to infect macrophages and DCs. SAMHD1 blocks HIV infection by dephosphorylating the deoxynucleotide triphosphates (dNTPs) of the cell, thereby blocking reverse transcription. When the virus infects a cell, Vpx is released, finds SAMHD1 in the nucleus and sends it off the proteasome to be degraded. For reasons that we still don’t fully understand, HIV-1 doesn’t have a Vpx. We’re interested to understand how SAMHD1 antiviral activity is regulated by the cell and why some lentiviruses need Vpx while others do not. HIV-1 encodes the related accessory protein, Vpr which is also virion-packaged and forms a complex with an E3 ubiquitin ligase. Vpr may counteract yet another host restriction and we’re trying to understand how that works.