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UK scientists may have found a way to destroy HIV's last refuge

A study by University of Oxford researchers 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.

Lucy Dorrell, M.D., and her team worked with Immunocore Ltd – a biotechnology company based in Oxfordshire – to investigate the potency of engineered immune-mobilizing T cell receptors-based drugs (ImmTAVs), designed to clear HIV-infected cells. Their study was published last month in Molecular Therapy.

Completely curing HIV is difficult as HIV targets CD4+ T-cells, part of the immune system. If untreated, active HIV destroys these cells, leading to AIDS. But the virus also can 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 harbor dormant HIV, known as HIV reservoirs. People can be treated and be 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.

ImmTAVs are two-headed proteins that assist the immune system in killing 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.

"We used cells from HIV patients who had had successful ART," Dr. Dorrell said. "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 percent of the infected cells were removed). This may be because, despite long-term ART, there is some degree of generalized 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 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.

Dr. 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."

The next step, Dr. Dorrell added, is to prove whether these effects seen in the lab 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," she added. "However, these positive results are cause for optimism."