Genetically engineered protein helps immune system see and kill cells containing dormant HIV.
UK scientists may have found a way to destroy HIV's last refuge. A study by Oxford University has confirmed that a treatment developed by a British company can remove the virus in its chosen hiding place, in laboratory conditions, offering hope of a viable treatment.
Professor Lucy Dorrell and her team at the University of Oxford worked with Immunocore Ltd - a UK biotechnology company based in Oxfordshire - to investigate the potency of novel engineered immune-mobilising T cell receptors-based drugs ('ImmTAVs'), designed to clear HIV-infected cells.
Completely curing HIV is difficult. HIV targets CD4+ T-cells, part of the immune system. If untreated, active HIV destroys these cells, leading to AIDS. But the virus can also enter some of the cells and remain dormant, so-called 'latent infection'. If the dormant HIV is reactivated, the process of active infection begins again.
While Anti-Retroviral Therapy (ART) stops the virus spreading, it is not able to eliminate the cells that harbour dormant HIV, known as HIV reservoirs. People can be treated successfully and become apparently free from the disease, but HIV bounces back if treatment is stopped and is able to keep re-seeding the reservoirs.
The final stage in defeating HIV is therefore to locate and destroy the lurking virus. If we can do that successfully, we may be able to cure HIV infections entirely.
ImmTAVs are two-headed proteins that can assist the immune system to kill HIV-infected cells. One end consists of a genetically engineered T-cell receptor that is fine-tuned to detect HIV proteins in an infected cell, even when they are present at very low levels. The other end is an antibody that binds to CD3, which is present on the CD8+ T-cells that kill virus-infected cells. The ImmTAV can therefore recruit a large number of CD8+ T cells and re-direct them to purge the HIV-infected cells.
Professor Dorrell said: 'We used cells from HIV patients who had had successful ART. When we added ImmTAV we saw that their CD8+ T-cells killed the latently infected CD4+ T-cells more efficiently than the patients' natural immune response. Furthermore, if we took CD8+ T-cells from healthy donors and added these alongside the ImmTAV, we saw an even stronger response (up to 85% of the infected cells were removed). This may be because, despite long-term ART, there is some degree of generalised malfunction in CD8+ T cells that has not been fully repaired. A test using only the donated CD8+ cells had no effect, confirming the essential role of the ImmTAV.'
Currently, researchers working on eradication of HIV are developing 'kick and kill' methods, where dormant HIV is reactivated and then a drug or vaccine is added in to eliminate the cells containing reactivated HIV. Having confirmed that ImmTAVs could be effective, the team combined them with the kick and kill approach in the lab.
Professor Dorrell said: 'We used latency-reversing agents, which wake up the HIV. Once we confirmed that the HIV was active again, we added ImmTAV. In four out of five cases, the process of reinfection was stopped completely.'
So are we close to a complete cure for HIV?
Professor Dorrell said: 'There is still work to do. This research was carried out in the lab but an effective cure has to take place in the patient. We need to prove that the effects we have seen can be replicated in people.
'ImmTAVs are likely to be one part of an HIV eradication strategy, rather than a complete cure. That strategy could comprise existing anti-retrovirals, ImmTAV and agents that address the weaknesses in HIV patients' CD8+ T-cells. However, these positive results are cause for optimism.'
Article: Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors, Hongbing Yang, Sandrine Buisson, Giovanna Bossi, Zoë Wallace, Gemma Hancock, Chun So, Rebecca Ashfield, Annelise Vuidepot, Tara Mahon, Peter Molloy, Joanne Oates, Samantha J Paston, Milos Aleksic, Namir J Hassan, Bent K Jakobsen and Lucy Dorrell, Molecular Therapy, doi: 10.1038/mt.2016.114, published online 12 July 2016.