Selected drugs with reported secondary cell-differentiating capacity prime latent HIV-1 infection for reactivation.
Reactivation of latent HIV-1 infection is considered our best therapeutic means to eliminate the latent HIV-1 reservoir. Past therapeutic attempts to systemically trigger HIV-1 reactivation using single drugs were unsuccessful. We thus sought to identify drug combinations consisting of one component that would lower the HIV-1 reactivation threshold and a synergistic activator. With aclacinomycin and dactinomycin, we initially identified two FDA-approved drugs that primed latent HIV-1 infection in T cell lines and in primary T cells for reactivation and facilitated complete reactivation at the population level. This effect was correlated not with the reported primary drug effects but with the cell-differentiating capacity of the drugs. We thus tested other cell-differentiating drugs/compounds such as cytarabine and aphidicolin and found that they also primed latent HIV-1 infection for reactivation. This finding extends the therapeutic promise of N'-N'-hexamethylene-bisacetamide (HMBA), another cell-differentiating agent that has been reported to trigger HIV-1 reactivation, into the group of FDA-approved drugs. To this end, it is also noteworthy that suberoylanilide hydroxamic acid (SAHA), a polar compound that was initially developed as a second-generation cell-differentiating agent using HMBA as a structural template and which is now marketed as the histone deacetylase (HDAC) inhibitor vorinostat, also has been reported to trigger HIV-1 reactivation. Our findings suggest that drugs with primary or secondary cell-differentiating capacity should be revisited as HIV-1-reactivating agents as some could potentially be repositioned as candidate drugs to be included in an induction therapy to trigger HIV-1 reactivation.
Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Takao
T
Shishido
Frank
F
Wolschendorf
Alexandra
A
Duverger
Frederic
F
Wagner
John
J
Kappes
Jennifer
J
Jones
Olaf
O
Kutsch
D015250:Aclarubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000188:drug therapy / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
D019380:Anti-HIV Agents; C011157:aclacinomycins; D003609:Dactinomycin; D015250:Aclarubicin