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Towards an HIV Cure: science and debate from the International AIDS Society 2013 symposium
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IAS Towards an HIV Cure Symposium, 29th-30th June 2013, Kuala Lumpur - Written for NATAP by David Margolis MD, UNC Chapel Hill and the Collaboratory of AIDS Researchers for Eradication (CARE) - (08/05/13)
Cure Strategies: "Viral and Immune-Targeted Interventions: Hit Me with Your Best Shot" - Oral Session at IAS 2013 Kulala Lumpur June 30-July 3 - (07/30/13)
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Towards an HIV Cure: science and debate from the International AIDS Society 2013 symposium
Damian FJ Purcell, Julian H Elliott, Anna-Laura Ross and John Frater
Retrovirology 2013, 10:134 doi:10.1186/1742-4690-10-134
Published: 13 November 2013
Abstract (provisional)
The International AIDS Society convened the multi-stakeholder "Towards an HIV Cure" symposium in Kuala Lumpur, Malaysia in 2013 to address the significant research challenges posed by the search for a cure for HIV infection. Current antiretroviral regimens select for a small reservoir of cells that harbour latent HIV provirus, produce few or no HIV virions, and resist detection or clearance by host immunity. The symposium examined basic molecular science and animal model data, and emerging and ongoing clinical trial results to prioritise strategies and determine the viral and immune responses that could lead to HIV remission without ART. Here we review the presentations that scrutinized the molecular mechanisms controlling virus expression from proviral DNA, and the intrinsic cellular restriction and immune mechanisms preventing viral production. Insights from the basic science have translated into new therapeutic strategies seeking HIV remission without ongoing therapy, and much interest was focused on these ongoing trials. We also summarise the emerging ethical issues and patient expectations as concepts move into the clinic.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.
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Conclusion
The "Towards a Cure" symposium captured the increasing research momentum based on the growing scientific understanding of the HIV reservoir and the increasing evidence from cases of HIV remission or cure. There is increasing interest in chemotherapeutic interventions promoting viral remission, and the first small steps have been encouraging. Early data from clinical studies with HDACi showed they were safe, well tolerated and successfully stimulated unspliced HIV RNA as the primary endpoint, providing optimism for broadly applicable viral reactivation strategies. However, viral RNA has not yet been linked with viral protein expression, and reduction in proviral load. Other biomarkers are needed that better correlate with elimination of the viral reservoir during curative interventions. Importantly, more HIV-specific activating drugs are following and these offer better specificity for HIV induction, and may potentially team with therapeutic vaccines or other strategies to eliminate cells containing reawakened HIV. But there is clearly a long way to go and key challenges lie in the search for combination interventions that not only lead to activation of latent HIV infection, but also significant decreases in the size of the HIV reservoir.
Evidence is mounting that early implementation of ART can assist in achieving viral control off therapy, possibly by preventing the seeding of virus into reservoirs that endure for the life of the patient. It remains to be resolved if the reservoir seeded during chronic infection differs from that laid down in the primary infection, and if it can be eliminated by chemotherapeutic intervention.
There are still large gaps in our understanding of the molecular mechanisms that restrict the expression and release of replication competent HIV from the different tissue reservoirs. While restrictive epigenetic and transcriptional programs largely underpin the limited HIV expression from most residual integrated proviruses, it is clear that various other molecular mechanisms can reversibly restrict viral expression, producing a diverse reservoir of residual latent provirus. An increasingly important impediment in the field is access to validated methods to measure the true size of the relevant replication competent latent virus reservoir.
The terms "sterilising" and "functional" cure have been used to describe patients who have achieved complete eradication or who control viral replication in the absence of ART, respectively [33]. Whereas the two concepts are valid, the meaning of 'functional' is unclear and - recognising the clear parallels with cancer therapeutics - the term "HIV remission without ART" has been proposed. The precise definition 'remission' still needs to be agreed, for example the duration of undetectable viraemia required or the risk of transmission. HIV cure research has benefited from strong interactions between basic scientists and clinicians, but it is clear that important insights provided by social scientists and members of the HIV community are required to determine the expectations surrounding HIV cure and the acceptability of different curative strategies. A trans-disciplinary approach must include non-HIV experts to bring new insights from the fields of oncology, other chronic infections and inflammatory diseases. Wide consultation is also needed to identify the appropriate conditions for interruption of ART and the protocols for monitoring viral recrudescence during treatment interruptions and the thresholds for reinstating therapy.
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