How HIV-1 lost control

C ells with a defective spindle get delayed—stuck in a mitotic checkpoint—but eventually escape mitosis. In vertebrate cells, say Daniela Brito and Conly Rieder (Wadsworth Center, New York State Department of Health, Albany, NY), that escape is a gradual limp rather than a sudden exit. The temporary stalling of the cell cycle in a checkpoint gives the cell time to repair damage before continuing. Ted Weinert and Lee Hartwell gave this phenomenon its name, but " they never viewed a checkpoint as leading to a permanent arrest, " says Rieder. Indeed, even in response to a problem that cannot be fi xed, such as high levels of the anti-microtubule drug nocodazole, many cells do leak through the mitotic arrest. In yeast and perhaps fl ies, the escape occurs via phosphorylation of Cdk1 or induction of a Cdk1 inhibitor. This adaptation pathway turns off the Cdk1/cyclin B complex, whose activity defi nes mitosis. A similar abrupt change was expected in vertebrate cells, via Cdk1 phosphorylation, induction of a Cdk1 inhibitor, or rapid degradation of cyclin B. " But it turns out it doesn't do any of these, " says Rieder. Instead, " human cells slowly degrade cyclin B over the course of time. " This slow, proteasome-dependent degradation of cyclin B was required for nocodazole-treated cells to escape from mitosis. The spindle assembly checkpoint remained intact and active throughout. Thus Brito and Rieder believe that vertebrate cells do not turn on a specifi c adaptation pathway. Instead there is a constant low level of cyclin B degradation that eventually reduces cyclin B levels below that needed to maintain a mitotic state. In plants the resultant exit may allow a change in ploidy, although its utility in mammals is less clear. A minor change during evolution converted the relatively benign monkey SIV viruses into deadly HIV-1, according tomany), and colleagues. They report that HIV-1, unlike most SIV strains, has lost the ability to protect its T cell hosts, and thus its human host, from death. The critical difference is in a virus protein called Nef, which increases virus infectivity and replication. But even more important than what HIV-1 Nef does may be what it does not do. The German group tested 30 different nef alleles in an HIV-1 vector. Most SIV Nef proteins down-regulated expression of the T cell receptor protein CD3 and thus blocked activation of infected T cells. Nef from …