amfAR, The Foundation for AIDS Research

More ‘Shocks’ in Strategies to Kill Latent HIV

By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.

The “shock and kill” approach to eradicating HIV from dormant cell reservoirs remains a key strategy in HIV cure research. In these monthly updates, we have reported on several drugs, originally developed to treat conditions ranging from epilepsy to cancer, that have the ability to “shock” virus out of its latent state. This leaves the virus vulnerable to attack by the immune system.

Dr. Melanie OttDr. Melanie OttUnfortunately, many of these drugs work much better in the test tube than in patients. Their therapeutic effects in patients are very modest, and they may lose effectiveness over time. Writing in the May issue of the journal Cell Host & Microbe, amfAR-funded scientist Dr. Melanie Ott and other amfAR Institute for HIV Cure Research colleagues at the Gladstone Institute of Virology and Immunology and the University of California, San Francisco, as well as researchers from Japan and the pharmaceutical company AstraZeneca, report a new avenue to shocking latent HIV.

Ott and associates note in the article that one leading hypothesis concerning the establishment of HIV latency posits that complexes of proteins and nucleic acids at the long terminal repeat (LTR)—the leading end of the viral DNA—regulate the ability of the virus to replicate. Several drug classes aimed at shocking the virus interact with these protein-nucleic acid complexes, known as nucleosomes, to help free the virus.

Using this reasoning, the researchers searched for new classes of drugs already in clinical development that may loosen the grip exerted by nucleosomes. They focused on cancer drugs in development that affect lysine methylation. They found that deletion of one enzyme, SMYD2, involved in this chemical pathway robustly shocked HIV from latency.

A series of experiments demonstrated that SMYD2 is indeed associated with the HIV LTR and that its mechanism of action is similar to that seen in cancer.

Therefore, using a small molecule inhibitor developed by AstraZeneca, known as AZ391, scientists may be able to shock HIV from the CD4+ T cells of HIV-infected individuals on suppressive antiretroviral therapy. This could prove to be a future drug.

The authors also concluded that this line of research underscores “the emerging ties between cancer and HIV treatment through shared drug targets.”

Dr. Laurence is amfAR’s senior scientific consultant. Dr. Johnston is amfAR’s vice president and director of research. 

For more information on SMYD2 and the HIV reservoir, read Dr. Johnston’s interview with A&U Magazine: