HIV Therapies – From “Hit Hard, Hit Early” to “Shock and Kill”

Since the outbreak of AIDS more than 30 years ago in the United States, HIV/AIDS is still one of the top ten causes of death worldwide [1]. One of the difficulties to cure HIV/AIDS is due to the lack of an effective HIV vaccine, although numerous laboratories are searching for it.

In 1995, David Ho first promoted a “hit hard, hit early” approach to eliminate HIV-1 infection in the early phase of the infection [2]. Yet, later on this approach was abandoned because of the high risk of side effects and the high cost of the treatment, this approach is still a milestone in the history of HIV/AIDS treatment. Nowadays, the standard approach for HIV/AIDS treatment is based on the standard antiretroviral therapy (ART) combining at least three antiretroviral (ARV) drugs to maximally suppress the HIV virus and stop the progression of HIV disease. Typical combinations include 2 nucleoside Reverse Transcriptase Inhibitors (NRTIs) + 1 Protease Inhibitor (PI) or 2 NRTIs + 1 non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) [3]. Clinical studies showed that ART is able to impressively decrease the mortality of AIDS patients.

It was gradually realized that one of the main reasons why this therapy is not a cure is that it lacks sensitivity. Some HIV proviruses actually lie dormant (viral lantency) within host cells after infection. In other words, those proviruses are invisible and out of reach from the therapy. This issue prompted Deeks et al. to propose the “Shock and Kill” strategy, published in Nature.

Expression of HIV proviruses is already known to be influenced by the epigenetic landscape or the chromatin context. For instance, Schröder et al. and Wu et al. revealed that HIV and murine leukemia virus (MLV) integrate preferentially in transcription units and at transcription start sites respectively. The idea of this strategy is to treat patients with vorinostat, a histone-deacetylase inhibitor to first reactive dormant viruses and then purge them all by maintaining ART. Although 100% activation of latent provirus is not achieved yet in culture, the concept of the “Shock and Kill” strategy still gives hope to cure HIV/AIDS.

The more we understand how HIV completes its infection, the more strategies we might be able to develop to cure AIDS. The whole process of HIV infection is multi-factorial, which causes the progress of the vaccine development to be more complicated than anticipated. If we could jump out of the traditional frame of vaccine design, an outstanding strategy might come up in the near future.

References

[1] http://who.int/mediacentre/factsheets/fs310/en/

[2] http://www.nejm.org/doi/full/10.1056/NEJM199508173330710

[3] http://www.ncbi.nlm.nih.gov/pubmed/23180144