Australian-developed blood cancer drug venetoclax has shown potential for killing ‘silent’ HIV-infected cells in a lab, and has delayed viral rebound in pre-clinical models, local researchers say.
Developed by scientists at Melbourne’s Walter and Eliza Hall Institute (WEHI), the BCL-2 inhibitor is best known as a treatment for CLL and has recently been approved for other blood cancers such as AML.
However, the medication is also showing promising antiviral effects for patients with latent HIV infection, which can be suppressed but not eliminated with currently-available antiretroviral therapy (ART).
Scientists believe the pro-apoptotic effect of venetoclax that underlies its efficacy against neoplastic cells can also be used to target HIV infected cells that also express similar ‘pro-survival’ proteins as seen in haematological cancer cells.
Using a humanised mouse model of HIV-1 infection and CD4+ T cells from people living with HIV on ART, researchers at WEHI found that extended venetoclax treatment was able to delay viral rebound by up to two weeks.
This effect was apparent when venetoclax was given alone, but increased to three weeks when it was given in combination with another drug, a BH-3 mimetic known as S63845, they noted in Cell Reports Medicine (link here).
Led by Dr Philip Arandjelovic (PhD), they theorised the effectiveness of venetoclax was likely due to differences between infected cells that persist on ART and other infected or healthy cells.
That distinction was “such that their pro-survival phenotype allows them to persist in a way that renders them susceptible to pro-apoptotic therapeutics,” they wrote.
“This phenomenon is also observed in clinical studies, in which malignancies tolerating and expressing the highest level of pro-apoptotic proteins are the most susceptible to venetoclax treatment.”
Commenting on the study, clinical immunologist and Kirby Institute director Scientia Professor Anthony Kelleher said the results were promising.
“The authors used two drugs with similar modes of action, increasing cell death by apoptosis of lymphocytes, but each blocked different targets within the cell survival pathways,” he noted.
“These results suggest that this combination of drugs could be explored in helping to find a pathway to an HIV cure or prolonged remission.”
“Although humanised mice are a standard model in which to study HIV therapeutics, results may not be transferrable to humans living with HIV, either in terms of efficacy or in terms of their side effect profile or toxicities, which can only be determined by systematic assessment through well designed human clinical trials.”
“The authors are proposing to explore the safety and efficacy of the approach through clinical trials.”