JCSMR School Seminar Series: Transcriptional Silencing of HIV-1 through promoter targeted siRNA: Induction and maintenance of viral latency, a new approach to stabilisation of viral reservoirs

Professor Tony Kelleher, Immunovirology and Pathogenesis program, Kirby Institute, Faculty of Medicine, The University of New South Wales.

Currently, although highly effective, antiretroviral therapy for HIV-1 infection is for life, without interruption.  Those stopping antiretroviral therapy have rapid recrudescence of viremia and disease progression. The viremia arises from the viral reservoir and standard anti-retrorviral therapy has limited impact upon this reservoir.

The next major advance in the therapy of HIV-1 infection will be one that effectively impacts on the viral reservoir. In CD4+ T memory cells, the reservoir is believed to consist of integrated virus in a latent state, silenced by epigenetic modifications of the nucleosomes associated with the viral promoter, the 5¹LTR.

Most strategies have been aimed at mobilising and then clearing this reservoir. Trials of global activation of T cells by cytokine stimulation (IL-2, IL-7) or T cell receptor stimulation (OKT3) to reactivate latent virus have failed.

Others propose activation of latent integrated virus via Histone Deactelyase inhibitors (HDACi). However, their efficacy is likely to be limited both by their non-specificity and by the fact that viral latency is determined by complex epigenetic machinery of which HDACs are only one component.

An alternate approach, which is far less explored, is to stablise the reservoir. We have taken a unique approach employing si/shRNAs targeting the 5¹LTR of HIV-1 to induce transcriptional gene silencing of the integrated virus which is highly specific, profound and prolonged; inducing a state akin to latency. This presentation will discuss the mechanisms underlying this process and present in vitro and in vivo data regarding the efficacy and possible feasibility of this approach.

Tony Kelleher is professor of Medicine at University of NSW, where he is head of the Immunovirology and Pathogenesis program at the Kirby Institute. He holds appointments at St Vincent’s Hospital Sydney, as a clinical Immunologist and Immunopathologist where he helps run the diagnostic services for HIV /AIDS and immunological conditions. His research interests encompass the immunovirology of HIV infection, particularly understanding the co-evolution of the virus and the T cell immune responses that control it. He has lead several trials of putative vaccines and anti retroviral therapies and coordinates a number of cohort studies in pathogenically informative populations such as long term non-progressors. He is developing a novel strategy for silencing viral transcription, based on novel siRNA technology, which is being developed towards testing in the clinic as a route towards a functional cure of HIV-infection.

Date & time

12–1pm 31 August 2012

Location

The Finkel Lecture Theatre, The John Curtin School of Medical Research, Building 131, Garran Road, ANU

Contacts

 Laura Vitler, Host: Charani Ranasinghe
 +61 2 6125 2589

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