Molecular detail of how HIV virus family subverts host cell’s own defences

08 April 2015

Cartoon representation of the Vpx-DCAF-SAMHD1 protein complex. DCAF1 is shown in light grey, SAMHD1 in magenta and Vpx (from the SIV virus) in blue. T3I AUG 2011

Image: Cartoon representation of the Vpx-DCAF-SAMHD1 protein complex. DCAF1 is shown in light grey, SAMHD1 in magenta and Vpx (from the SIV virus) in blue.

The HIV family of lentiviruses carry 'accessory proteins' that recruit a host cell's own machinery to break down one of its antiviral defence proteins.

Vpx, accessory proteins found in HIV-2 and SIV (close relatives of HIV-1, the main cause of the global AIDS pandemic) target a host antiviral defence protein called SAMHD1. To do this, they manipulate a host receptor protein called DCAF1.

By uncovering the three-dimensional structure of Vpx bound to SAMHD1 and DCAF1, Francis Crick Institute researchers currently based at Mill Hill Laboratories have revealed how the Vpx from different viruses use different strategies to recruit SAMHD1.

For their study, the team used X-ray crystallography to determine the structure of Vpx from an SIV virus isolated from mandrill monkeys, as well as DCAF1 and SAMHD1. The scientists compared their result with a structure they had previously determined of a complex containing a Vpx from another lentivirus to reveal how all Vpx proteins interact with DCAF1 in a common manner but differ in the way they recruit SAMHD1.

Dr Ian Taylor of the Crick said: "It is now clear that lentiviruses (the virus family that includes HIV) carry accessory proteins that have the sole purpose of targeting cellular factors that inhibit retroviral infection.

Commenting on the implications of the work for treating HIV/AIDS, "The 3D structure of this protein complex reveals in molecular detail how these factors have adapted to be able to this."

Dr Taylor added: "Disrupting the interaction of viral accessory proteins such as Vpx with the host cell factor DCAF1 would be a completely new way of disrupting HIV-1 replication by boosting the cell's own natural defence to the virus."

The paper, Molecular Determinants for Recognition of Divergent SAMHD1 Proteins by the Lentiviral Accessory Protein Vpx, is published in Cell Host and Microbe.

  • Francis Crick Institute scientists have uncovered important detail about how members of the HIV virus family turn a host cell on itself to enable infection. It's hoped that the work will lead to a completely new way to treat HIV/AIDS in the future.
  • According to statistics from the World Health Organization, 35 million people were living with HIV in 2013.
  • The research was supported by supported by the Medical Research Council, the Wellcome Trust, the European Molecular Biology Organization, the European Commission and the American Foundation for AIDS Research.