Eradication of HIV is currently the focus of major research efforts. The scale of this challenge is illustrated by speed at which new concepts have required re-examination. Initial estimates of the rate of decay of the HIV reservoir under combination antiretroviral therapy were rapidly revised from 3 to 73 years. ‘Functional’ cure following haematopoietic stem cell transplantation has to date been observed in a single individual. Hopes for similar results in the ‘Boston patients’ were recently dashed when they relapsed without warning after several months off antiretroviral therapy. The size of the HIV reservoir was revised upwards when new assays revealed the extent to which long-lived CD4+ T cells harbour dormant yet genetically intact proviruses. And clinical trials evaluating the latency-reversing potential of agents such as the histone deacetylase (HDAC) inhibitor, vorinostat, raise questions about whether HIV reactivation can be achieved without global T cell activation.

HDAC inhibitors, first mooted as a therapy to decrease HIV reservoirs over 10 years ago, have been advocated as part of a ‘Shock and kill’ strategy. While more potent agents are in the pipeline, the field is once again facing sobering reality as emerging data suggest that vorinostat delivers little more than a tickle rather than a shock and can also upregulate diverse normally repressed host genes with as yet unknown consequences.

The specifics of the kill, meanwhile, have been somewhat ignored. This is not surprising, given that it will likely depend on induction of potent cytolytic T cell responses, in sufficient numbers, in the right place, at the right time - a concept that appeared to founder with the disappointing results of the first efficacy trial of a T cell-inducing vaccine, the Step Study. However, once again, assumptions have been overturned by recent data showing that a T cell-based vaccine approach can clear the reservoir following AIDS virus infection in monkeys. Collectively, these studies are an important reminder that unexpected setbacks and successes can each provide valuable insights for the development of immunotherapeutics for HIV eradication. Furthermore, advances in systems immunology and gene therapy mean there is no shortage of tools for testing new concepts. Just over 3 years ago, HIV cure was still a hypothesis; while there has been much progress since then, it is vital that efforts to build on this success are sustained. This topic aims to stimulate ideas for innovative approaches to reducing the HIV reservoir that are clinically testable, deliverable and scalable.

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