Silencing HIV: a new approach in viral reservoir stabilization

HIV is without a doubt one of the greatest viral threats faced by humanity in the 21st century. With a life cycle  that can be as short as 1-2 days from viral cell infection, the virus is able to replicate and in turn release additional virus cells amongst the host. In combination with reverse transcription, the virus is able to mutate quite rapidly and most threateningly; at high genetic diversity1. In a recent discussion by Doctor Tony Kelleher from the Kirby Institute, UNSW Medicine; in conjunction with Macquarie University Hospital’s medical seminars, Doctor Kelleher explains his cutting edge research into potential HIV treatments.

CART – Combined Anti-Retroviral Therapy

As potential vaccinations for HIV/AIDS are currently some years away, HIV must be treated rather than cured. Today the most predominant treatment for HIV is combined Antiretroviral Therapy or cART2. Doctor Kelleher explains whilst cART is somewhat of an effective treatment it has a number of pitfalls; cART does not impact on the viral reservoir. A viral reservoir refers a cell type or location within the host in which a virus’ replication primarily  takes place; it is more stable than the remaining actively replicating virus1. It is this persistence of a viral reservoir in HIV that makes the virus difficult to both treat and cure. If cART is interrupted chances of morbidity and mortality are greatly increased, meaning that cART is a treatment for life; which in many cases can be problematic towards the individual in treatment2. Furthermore prolonged treatment with cART can lead to potential health issues of its own with an acute toxicity build up with the patient2.

Berlin Patient

The Berlin Patient refers to two individuals that have been known to be functional cleared of HIV. The most known patient is Timothy Ray Brown, found cured in 2008 as a result of an allogeneic hematopoietic stem cell transplant3. The donor was found to be homozygous for CCR5 delta32 deletion and henceforth meant the HIV was unable to enter the host’s cells without a functional CCR5 gene; theoretically curing the patient3. The success of this treatment has led to the inspiration for a number of unique and novel studies such as siRNA and post transcriptional gene silencing.

siRNA and Post Transcriptional Gene Silencing

The discovery of small interfering RNA or silencing RNA (siRNA) is only recent and was first described in plants as a ‘post-transcriptional gene silencing’4. siRNA have be proven to play a crucial role in gene expression and therefore have generated a substantial interest as potential treatments for viruses such as HIV-1. The targeting of HIV-1 promoters in vitro siRNA has already been shown to silence HIV-1 gene replication4(Figure 1). Dr Kelleher outlines that siRNA and post transcriptional gene silencing has a number of advantages over the traditional cART; once the HIV-1 gene expression is switched off there is no viral turnover and less risk of resistance and viral escape within the patient. This method also allows for the stabilization of the viral reservoir and the patient to cease cART.

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Figure 1: Twostep process of siRNA gene silencing5

The implications of Doctor Kelleher’s research is huge, the effective treatment of HIV-1 will not only prolong the lives of patients, but vastly improve their quality of living. The advancement of treatments such as this lends to our understanding of this deadly virus and how it operates, bringing us one step closer towards a cure.

References

  1. Blankson, J.N., Persaud, D. & Siliciano, R.F. 2002. The challenge of viral reservoirs in HIV-1 infection. Annual Reviews of Medicine, 53: 557-593.
  1. Schouten, J., Cinque, P., Gisslen, M., Reiss, P. & Portegies, P. 2011. HIV-1 infection and cognitive impairment in the cART era: a review. AIDS, 25: 561-575.
  1. Yukl, S.A., Boritz, E., Busch, M., Bentsen, C., Chun T-W., Douek, D., Eisele, E., Haase, A., Ho, Y-C., Hutter, G., Justement, J.S., Keating, S., Lee, T-H., Li, P., Murray, D., Palmer, S., Pilcher, C., Pillai, S., Price, R.W., Rothenberger, M., Schacker, T., Siliciano, J., Siliciano, R., Sinclair, E., Strain, M., Wong, J., Richman, D. & Deeks, S.G.2013. Challenges in Detecting HIV Persistence during Potentially Curative Interventions: A Study of the Berlin Patient. PLoS Pathogens, 9(5): e1003347.
  1. Suzuki, K., Marks, K., Symonds, G., Cooper, D.A., Kelleher, A.D., Hattori, S., Okada, S., Ahlenstiel, C., Maeda, Y., Ishida, T., Millington, M. & Boyd, M. 2013. Promoter targeting shRNA suppresses HIV-1 infection in vivo through transcriptional gene silencing. Molecular Therapy – Nucleic Acids, 2: e137.

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  1. McManus, M. and Sharp, P. 2002. Gene silencing in mammals by small interfering RNAs, Nature reviews genetics, 3(10): 737-747.

 

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