Kick & Kill: Looking to cure HIV

Ever since the Human Immunodeficiency Virus (HIV) was discovered and identified as the cause of AIDS, scientists have been on the hunt for a cure, which is proving to be elusive.

The HIV virus remains concealed in the reservoir cells; for this reason, the HIV infection, which is in remission with antiretroviral drugs (ART), becomes active again as soon as ART is discontinued. Killing these latent reservoirs is therefore essential to achieving cure.

Scientists are better equipped today, both with knowledge and technology, which raises hopes of finding a cure.

One among the curative strategies, which has been explored the most, is the ‘kick and kill’ strategy. It is based on the premise that “kicking” (reactivating) the latent reservoirs would make the hidden HIV visible to the immune system, which then “kills” (destroys) the reactivated virus and thus eliminates the latent reservoir. However, the results of trials using the kick and kill strategy have not been very encouraging.

The RIVER study, the first proof of concept trial is the latest to investigate the “kick and kill” strategy in primary HIV infection using vorinostat as the “kick” and the boosted immune response, using a vector vaccine (HIV-specific) designed to train the immune system to recognize the reactivated virus as the “kill”.

Vorinostat is a histone deacetylase (HDAC) inhibitor with antineoplastic activity. It is a gene stimulating drug, which enables inactive genes to switch back on, so the cells become active again. The study recruited 60 men recently diagnosed with HIV infection and had the virus under control with a minimum 12 weeks of ART before entering the study. The study participants were randomly assigned to ART alone or the “kick” and “kill” therapies (ARTVV) in addition to ART, at six sites in the UK.

First, the vaccine was administered in two doses, one at baseline and second, 8 weeks later. Then vorinostat was administered as one dose every three days for the next 30 days after week eight.

The findings of the randomized controlled trial were presented at the recently concluded International AIDS Societys annual meeting in Amsterdam, Netherlands (AIDS 2018). But, the results were not very encouraging. Despite evidence of strong vaccine-induced HIV-specific T-cell immunity (increased number of HIV-specific CD4 and CD8 cells) and vorinostat activity (increase in HIV gene expression), there was no impact on measures of HIV reservoir compared to ART alone. They did not reduce the cells containing HIV DNA. Those who had received the kick and kill drugs in addition to ART had similar levels of infected reservoir cells than those who were given only the standard ART therapy.

Professor Sarah Fidler of Imperial College London and Chief Investigator of the study said: “Finding an HIV cure means orchestrating a lot of things. We have to generate new ideas and turn them into trials that will give meaningful results, we have to agree what research tests will tell us whether things are working or not, we need to very carefully monitor study participants and most importantly we need to make sure any trial intervention is safe. RIVER achieved all these things but sadly not the evidence of a possible HIV cure yet.”

The reasons for failure of the ARTVV regimen to reduce the latent reservoir are being examined. “The important thing to realise is that despite these disappointing results, it does not mean that the basis of the approach is wrong,” said Professor John Frater of the University of Oxford, who is the co-principal investigator.

(Source: Science Daily)

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