Cancer drug kills latent HIV cells and delays virus re-emerging

Fresh hopes for a functional cure for AIDS have been raised by new research from Australia – showing that the blood cancer drug venetoclax kills HIV latently infected cells remaining in the body after antiretroviral therapies, and also delays HIV reactivation.

A treatment for blood cancer has been found to kill ‘silent’ HIV cells – raising fresh hopes of finally finding a cure for the disease.

Australian researchers discovered that venetoclax, a standard-of-care treatment for leukaemia for almost a decade, depletes HIV latently infected cells remaining in the body after Antiretroviral Therapies (ART).

They also demonstrated that venetoclax delays the reactivation of the HIV virus for up to two weeks after ART treatment is stopped. Furthermore, using venetoclax in combination with drug candidate S63845 delays this viral ‘rebound’ significantly.

ART is highly effective in suppressing the HIV virus but cannot cure it – and if people living with AIDS stop their treatment, latent HIV cells in the body help the virus to reactivate quickly. Finding a therapy that can kill off these ‘silent’ cells is therefore crucially important to the 39 million people living with HIV globally, including almost 30 million who are receiving ART.

“In attacking dormant HIV cells and delaying viral rebound, venetoclax has shown promise beyond that of currently approved treatments,” said the study’s co-first author, Dr Philip Arandjelovic.

“Every achievement in delaying this virus from returning brings us closer to preventing the disease from re-emerging in people living with HIV. Our findings are hopefully a step towards this goal.”

The research team – from The Walter and Eliza Hall Institute and The Peter Doherty Institute in Melbourne – injected humanised mice with HIV, and then used ART to suppress it. The mice were subsequently dosed with venetoclax for six weeks, which delayed the virus reactivating for up to two weeks after ART was stopped.

Co-first author, Dr Youry Kim, said venetoclax potently reduced the amount of intact viral DNA in patient cells when studied in the laboratory – indicating that “venetoclax is selectively killing the infected cells, which rely on key proteins to survive.

“Venetoclax has the ability to antagonize one of the key survival proteins," she added.

Meanwhile, using venetoclax and S63845 together not only decreased HIV viral loads in the mice, but also “delayed time to viral rebound by up to 4-fold after ART cessation”, despite this combined therapy lasting for just three weeks. Both venetoclax and S63845 act on the same pro-survival pathway in cells.

The group also achieved exciting results in separate experiments on cells donated by people living with AIDS - which showed “a significant dose-dependent reduction in total integrated HIV-1 DNA” following venetoclax treatment, especially amongst a sub-group of naive and effector memory CD4+ T cells.

The group stressed that their study had a number of limitations, including the use of mice - which were only able to withstand six weeks of being given venetoclax, limiting the duration of the study – and continued uncertainty about which specific reservoir of HIV-1 DNA was being depleted by the treatment.

“The optimal strategy for eliminating the HIV-1 reservoir remains unclear and may well require a combinatorial regimen,” they wrote in the journal Cell Reports Medicine.

“(However) importantly, our results demonstrate... a potentially feasible and effective clinical approach toward achieving a cure for HIV-1.”

The results of the study are now being translated into a Phase I/IIb clinical trial in Denmark and Australia, aimed at assessing the safety and tolerability of venetoclax in people living with HIV and receiving ART. But given that venetoclax already has a well-documented pharmacological and toxicological profile, and “few major side effects relative to other chemotherapeutics”, the group believes it is “a prime candidate for further clinical investigation in the setting of HIV-1 cure research.”

“It's exciting to see venetoclax, which has already helped thousands of blood cancer patients, now being repurposed,” said Professor Sharon Lewin, a joint corresponding author of the report. “(It could) help change the lives of people living with HIV and put an end to the requirement for life-long medication.”