Abstract
Virus assembly and maturation proceed through the programmed operation of molecular switches, which trigger both local and global structural rearrangements to produce infectious particles. HIV-1 contains an assembly and maturation switch that spans the C-terminal domain (CTD) of the capsid (CA) region and the first spacer peptide (SP1) of the precursor structural protein, Gag. The crystal structure of the CTD-SP1 Gag fragment is a goblet-shaped hexamer in which the cup comprises the CTD and an ensuing type II β-turn, and the stem comprises a 6-helix bundle. The β-turn is critical for immature virus assembly and the 6-helix bundle regulates proteolysis during maturation. This bipartite character explains why the SP1 spacer is a critical element of HIV-1 Gag but is not a universal property of retroviruses. Our results also indicate that HIV-1 maturation inhibitors suppress unfolding of the CA-SP1 junction and thereby delay access of the viral protease to its substrate.
DOI:
http://dx.doi.org/10.7554/eLife.17063.001
Viruses like HIV must undergo a process called maturation in order to successfully infect cells. Maturation involves a dramatic rearrangement in the architecture of the virus. That is to say, the virus’s internal protein coat – called the capsid – must change from an immature sphere into a mature cone-shaped coat. Notably, this maturation process is what is disrupted by the protease inhibitors that are a major component of anti-HIV drug cocktails.
Structural changes in small portions of the capsid protein, termed molecular switches, commonly trigger the viral capsids to reorganize. The HIV capsid has two of these switches, and Wagner, Zadrozny et al. set out to understand how one of them – called the CA-SP1 switch – works.
Solving the three-dimensional structure of the immature form of the CA-SP1 switch revealed that it forms a well-structured bundle of six helices. This helical bundle captures another section of the capsid protein that would otherwise be cut by a viral protease. The CA-SP1 switch therefore controls how quickly the protein is cut and the start of the maturation process.
Wagner, Zadrozny et al. then discovered that other small molecule inhibitors of HIV, called maturation inhibitors, work by binding to and disrupting the transformation of the CA-SP1 switch. Finally, further experiments showed that the formation of the CA-SP1 helical bundle controls when the immature capsid shell forms and coordinates the process with the capsid gaining the genetic material of the virus.
The new structure means that researchers now know what the HIV capsid looks like at the start and end of maturation. The next challenge will be to figure out exactly how the capsid changes from one form to the next as HIV matures.
DOI:
http://dx.doi.org/10.7554/eLife.17063.002
