HDAC inhibitors and their possible consequences

When HIV infects a cell of the immune system, a number of possibilities can occur. One pathway is that HIV takes over the cell and redirects the cell to make more copies of HIV. In other cases, HIV can infect a cell but stay dormant until the cell is activated and virus production ensues. Trying to eliminate this dormant HIV will be critical in effecting a cure.

Researchers in the U.S. have proposed using the anti-cancer drug vorinostat (SAHA, Zolinza), which is an inhibitor of the enzyme HDAC (histone deacetylase). In HIV-positive people, this enzyme helps to keep HIV in a latent state in resting cells. By inhibiting HDAC, researchers hope to activate HIV-infected cells in ART users. Even though new copies of HIV will be created from the use of HDAC inhibitors, researchers hope that newly produced HIV should not be able to infect many cells because study volunteers will be using ART. In theory, after prolonged exposure to vorinostat and related drugs, researchers hope that they will be able to reduce the number of HIV-infected cells in the body, either to extremely low levels or altogether. However, this reduction in the burden of HIV-infected cells in the body arising from the use of HDAC inhibitors has not yet been proven. Moreover, the long-term safety and effectiveness of potent HDAC inhibitors such as vorinostat must be assessed in HIV-positive people. These drugs are generally used for the treatment of cancers and have side effects, some mild, others serious.

An unknown future

Although HDAC inhibitors are supposed to affect the enzyme that keeps HIV in a latent state, it is possible that the same enzyme keeps other, perhaps poorly understood, retroviruses also in a latent state. Specifically: Humans carry within their DNA traces of retroviruses other than HIV, which have evolved with us over millions of years. These traces are not sufficient to cause new infections; however, there is the theoretical possibility that by unleashing histone deacetylase with HDAC inhibitors these traces of old retroviruses may combine with HIV, forming new retroviruses. The consequences of this for a person’s health are not known. However, there have not been reports, at least so far, of new viruses arising from HIV-positive people treated with HDAC inhibitors.

In this issue of TreatmentUpdate, we report on clinical trials of vorinostat, a relatively potent inhibitor of HDAC.

—Sean R. Hosein

REFERENCES:

1. Cillo A, Sobolewski M, Coffin J, et al. Only a small fraction of HIV-1 proviruses in resting CD4+ T cells can be induced to produce virions ex vivo with anti-CD3/CD28 or vorinostat. In: Program and abstracts of the 20^th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta, U.S. Abstract 371
2. SenGupta D, Tandon R, Vieira RG, et al. Strong human endogenous retrovirus-specific T cell responses are associated with control of HIV-1 in chronic infection. Journal of Virology. 2011 Jul;85(14):6977-85.
3. Jones RB, Garrison KE, Mujib S, et al. HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. Journal of Clinical Investigation. 2012 Dec 3;122(12):4473-89.