A completely new way of treating HIV, the virus that causes AIDS, is on the horizon after scientists discovered a possible way to boost a host cell's own defences.
Researchers at the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute) revealed how 'accessory proteins' carried by the HIV virus - recruit a host cell's own machinery for breaking down proteins to disable its own anti-viral defences.
The findings suggest that a new type of HIV drug could disrupt replication of the virus by targeting this unique relationship between the viral accessory proteins and host cell proteins.
HIV is part of a family of viruses called lentiviruses, which replicate slowly and have a long incubation period. The family includes two HIV viruses - HIV-1, which is responsible for the majority of cases of human AIDS, and HIV-2, which also infects humans but is less infectious and less virulent. The lentivirus family also includes viruses that infect monkeys, apes and other mammals.
Ian Taylor of NIMR explained: "Lentiviruses contain accessory proteins - these have evolved to counteract the defence proteins in host cells that inhibit their infection."
One such host cell defence protein, which inhibits HIV-1 infection, is called SAMHD1. Researchers already knew that HIV-2 and related lentiviruses overcome SAMHD1 using viral accessory proteins called Vpx or Vpr. These target and recruit SAMHD1 to be degraded by the host cell's own protein degradation machinery.
"But we didn't know precisely how these viral proteins take over the host cell's protein degradation machinery to use in this way."
To investigate, Dr Taylor's team used X-ray crystallography to determine the structure of a protein complex containing Vpx, SAMHD1 and a component of the host cell degradation machinery called DCAF1.
This structure showed that Vpx wraps around DCAF1 and creates a new surface that binds to SAMHD1 and recruits it to be degraded by the cell. Through this mechanism, the viral accessory protein Vpx subverts the cell's normal protein degradation pathway to inactivate its viral defence system.
Dr Taylor said: "It is now clear that lentiviruses carry accessory proteins with the sole purpose of targeting host cell factors that inhibit retroviral infection. Our results reveal in molecular detail how they are able to do this".
He added: "Disrupting the interaction of viral accessory proteins, Vpx and Vpr with cellular factors like DCAF1 would be a completely new way of disrupting HIV-1 replication, by boosting the cell's own natural defence to the virus. This work therefore has implications for a new type of HIV therapy using drugs to target the unique molecular interface between the viral accessory protein and the cellular factors they target."
The paper, Structural basis of lentiviral subversion of a cellular protein degradation pathway, is published inNature.
