Microbiology Select

The interactions between virus proteins and host cells are intricate and impact diverse processes. Recent papers explored in this issue's Microbiology Select reveal unexpected mechanisms by which viruses interact with host cells to facilitate infection, promote replication of their genomes, and foster horizontal gene transfer. The Tat (transactivator of transcription) protein of the human immunode-ficiency virus (HIV) hijacks host P-TEFb (positive transcription elongation factor b) to promote HIV transcription. A recently published structure by Tahirov et al. (2010) provides insight into how this interaction shapes the function of P-TEFb. P-TEFb is a complex consisting of human cyclin-dependent kinase 9 (Cdk9) and cyclin T1, and the structure provides an explanation for more than 1100 tolerated mutations in Tat. It also reveals that although the major interface of Tat is with cyclin T1, it also interacts with the regulatory T loop of Cdk9. The work shows that Tat affects the conformation of P-TEFb, including a change in the sub-strate-binding surface of the kinase. The authors propose that the unfolding of the a helix HC of cyclin T1 observed with Tat binding could contribute to the release of P-TEFb from HEXIM, a protein that maintains P-TEFb in an inactive form. In addition to this key mechanistic insight into Tat function, the structure opens a window on possible therapeutic strategies that would seek to block activity or formation of the complex. On this point the authors raise the appealing prospect that the conforma-tional change exhibited upon Tat binding could be advantageous for the design of inhibitors that only interfere with the function of the Tat,P-TEFb complex, leaving the native function of P-TEFb unimpaired. During infection of host cells, coronaviruses induce the formation of double-membrane vesicles that are thought to be the location of virus genome replication. Despite the importance of this step in the coronavi-rus life cycle, it remains uncertain precisely where this membrane comes from. Findings by Reggiori et al. (2010) now provide evidence that the virus commandeers an element of the endoplasmic reticulum (ER) quality-control machinery in the formation of the double-membrane vesicles. They demonstrate that double-membrane vesicles induced by mouse hepatitis virus (MHV) are characterized by the presence of short-lived ER chaperones, such as EDEM1 (ER degradation-enhancing alpha-mannosidase-like 1) and OS-9, which recognize misfolded proteins as part of ER-associated protein degradation (ERAD). Prior work has shown that EDEM1 is removed from the ER in a process called ERAD tuning, and the …