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Cancer drug shows promise in HIV cure study in humanized mice
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IAS 2023 Press Release
A widely used cancer drug can be used to deplete HIV latently infected cells and delay viral rebound in humanized mice, according to a study from a team of researchers in Australia.
In the study, venetoclax - which is currently used to treat certain blood cancers - delayed viral rebound in a pre-clinical model of latent HIV infection and depleted HIV DNA ex vivo in CD4+ T-cells from people living with HIV who were on antiretroviral therapy.
Presented by Philip Arandjelovic of the Walter and Eliza Hall Institute of Medical Research in Melbourne, the study was a collaboration with the Doherty Institute, a joint venture of the University of Melbourne and Royal Melbourne Hospital, also based in Melbourne. The team assessed whether inhibiting host pro-survival proteins with venetoclax could preferentially prime latent cells to die and clear the viral reservoir.
In the CD4+ T cells treated ex vivo in a dose-dependent manner, intact DNA displayed a median-fold change of 0.58x with 100 nanomolars of venetoclax. The drug induced higher rates of death in naïve and central memory T-cells compared to other T-cell subsets, and cells with higher expression of transcripts of pro-apoptotic BH3-only proteins were overrepresented in the venetoclax-sensitive population.
In the humanized mouse model, researchers evaluated time to viral rebound following cessation of antiretroviral therapy. When dosed on weekdays for six weeks, venetoclax significantly delayed viral rebound after cessation of antiretroviral therapy. When combined with the MCL1 inhibitor S63845 and dosed on weekdays for three weeks, the combination achieved a longer delay in viral rebound compared to either intervention alone; the median time to viral rebound was three weeks.
"These are very encouraging results," Lewin, a member of the study team, said. "It's exciting that venetoclax will soon be tested in a clinical trial in Australia and Denmark as a potential pathway to an HIV cure."
Abstract and session: Venetoclax, alone and in combination with the BH3-mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice, Track A late-breaker session (5735, Track A)
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