HIV Plays (and Wins) a Game of T Cell Brinkmanship

Viruses are locked into an adaptive arms race with the host immune system: the immune system adapts to recognize the virus, the virus adapts to evade the immune system, the cycle repeats. But in the case of HIV, it seems, sometimes it’s good to be recognized. The cellular branch of the immune system comprises T cells that recognize specific short peptides (epitopes) clipped from viral proteins and displayed on the surface of infected cells. Like antibodies, the receptors borne by T cells are ‘‘adaptive’’, that is, they can vary and be selected for if they detect something useful (like viruses). As ever with the immune system, things are of course somewhat more complicated—there are several major types of T cells that do different jobs. The ones that concern us here are the T helper cells (TH cells), which need to be activated by epitopes displayed on the surface of ‘‘professional antigen-presenting cells’’, and can then collaborate with another type of T cell—the cytotoxic T cells (CTLs)—to destroy infected cells. This means that there’s a strong incentive for the corresponding epitopes of the viral proteins to mutate, allowing the virus to escape T cell surveillance and survive for longer in the host body. As a result, most viral genomes tend to vary substantially in the regions that encode T cell epitopes. But HIV stands out as an exception to this tendency—their T cell epitopes seem to vary less than the rest of the genome. Why? Several theories have been advanced to explain this counterintuitive result, but a new study by Rafael Sanjuán, José Alcamı́, and colleagues in PLOS Biology provides evidence for a tantalizing and potentially important new explanation. It revolves around another peculiarity of HIV—the fact that it infects the very cells that are responsible for the cellular immune response—the T cells themselves. The authors carefully scrutinized a wide range of HIV genome sequences to look for patterns of variation. For comparison, they also checked sequences of the more conventional hepatitis C virus (HCV). HCV doesn’t infect T cells, and its T cell epitopes vary in an attempt to fly under the T cell radar. HIV does infect T cells, and its T cell epitopes are puzzlingly unchanging. After ruling out a number of alternative explanations, the authors