Dr Stephane Hue, a researcher supported by our BRC, together with a team at Guys St Thomas BRC, have discovered a new HIV-1 restriction factor, an important step in research into the development of new therapies.
Until now only four HIV-1 restriction factors have been identified. In this latest study, with results published in Nature last month, researchers have identified a fifth HIV-1 restriction factor ‘MX2’.
Restriction factors are proteins that protect against viruses and form a part of a person’s innate antiviral responses. If researchers can harness these to use as protection against viruses, there is the potential to develop new therapies for HIV-1.
This potential to develop new therapies is invaluable in a situation where antiretroviral drugs have been through several generations and new treatments are constantly needed.
APOBEC3G was the first HIV-1 restriction factor identified in 2002. Since then tetherin, TRIM5α, SAMHD1 and now MX2 have joined the APOBEC family of proteins as HIV-1 restriction factors.
A key concept relating to restriction factors is that viruses such as the most common type of HIV – HIV-1 – encode proteins so they can evade restriction. This situation with the host producing restriction factors and the virus deploying counter-measures leads to something of an ‘arms race’ making the therapeutic use of restriction factors less than straightforward.
Therapeutic use of restriction factors
In work supported by the University College London Hospitals and Great Ormond Street BRCs, Professors Waseem Qasim and Greg Towers described escape-resistant anti-HIV restriction factors. Click for link to paper in Human Gene Therapy
These restriction factors are based on fusion of TRIM5 and Cyclophilin A proteins, and have arisen twice in primates, making the primates highly resistant to primate lentiviral replication. Professors Qasim and Towers demonstrated that human TRIM5CypA variants strongly suppress HIV-1 in cells in the laboratory and in model systems and the virus does not escape restriction mediated by the TRIMCypA variants.
In a programme of work linking our BRC, Great Ormond Street and Guy’s and St Thomas’ BRCs, Professors Qasim and Towers are preparing escape-resistant anti-HIV restriction factor human TRIM5CypA to use in a pilot study of HIV eradication in patients unable to tolerate anti-retroviral therapy.
Although eradication of HIV has been achieved in patients undergoing stem cell transplantation, finding matched donors to provide HIV refractory cells is rare. The aim of this pilot clinical trial is to transfer TRIM5CypA proteins into a patient’s immune cells and use these modified T cells for immune reconstitution.
Lentivirus mediated gene transfer will be used to introduce TRIM5CypA into cells. Production of the vectors for gene transfer is underway, and the aim is to begin a phase I clinical trial within three years.
