By Karine Dubé and Joseph Tucker
The National Institutes of Health (NIH) held the Strategies for an HIV Cure meeting on October 15 – 17, 2014 in Bethesda, MD. Over 600 scientists, patient advocates, industry partners and NIH representatives registered for the meeting, packing the Natcher auditorium.
Dr. Anthony Fauci, NIAID Director, opened the meeting, asking everyone to put each specific disease and epidemic into perspective. While the Ebola virus is a disaster in West Africa that has now reached global proportions, the total number of patients who died of Ebola in the recent past is equal to the number of HIV-related deaths in one day. There are definite rationales for intensifying HIV cure/remission research, including the challenges of drug adherence, resistance, cumulative toxicities and negotiating the “care continuum.” Dr. Fauci further emphasized that an HIV cure/remission should be simple, safe and scalable as much as possible.
Key highlights in the 7 key areas in the search for an HIV cure/remission included:
- Regulatory, Social, Ethical and Community Aspects of HIV Cure Research
Veronica Miller, from the Forum for Collaborative HIV research, discussed regulatory issues in HIV cure research and the need to appreciate “evolving consensus” in the field, particularly related to sensitive topics, such as analytical treatment interruption. Joseph Tucker highlighted the work of the searcHIV working group on the unintended and intended implications of HIV cure research. Jeff Taylor, leader of the Collaboratory of AIDS Researchers for Eradication (CARE) Community Advisory Board, discussed the importance of community engagement in HIV cure research.
Throughout the meeting, the community advocates brought up the importance of using language carefully around HIV cure/remission research. Indeed, HIV cure/remission interventions will unlikely be “curative” in the short-term.
- Strategies to Reverse Latency
One highlight in the areas of latency-reversing agents included Dr. David Margolis’ update on the Collaboratory of AIDS Researchers for Eradication (CARE). Lead candidate latency-reversing agents at this time include histone deacetylase inhibitors (HDACs), PKC agonists, natural projects, bromodomain inhibitors as well as compounds emerging from new screens. More work will need to be done in the next few years with individual drugs, including determining how to optimally use them in combination. Large reductions in the viral reservoirs will be needed to affect viral rebound and there will likely be significant patient-to-patient variations in response to these compounds.
- Gene Editing and Cell-Based Strategies:
Data are starting to emerge in the fields of gene editing and cell-based strategies. There have been attempts at reproducing Timothy Brown’s cure. These studies include aspects of hematopoetic stem cell transplantation (HCT) as a platform to purge the latent HIV reservoir as well as the role of the allograft. Scientists have demonstrated that uninterrupted ART is possible during HCT, but very unlikely to lead to viral reservoir eradication by itself.
- Strategies to Measure the Latent HIV Reservoir: Improved Assays and Biomarkers
Dr. Robert Siliciano gave the keynote lecture on the latest developments in the strategies to measure the latent HIV reservoir. The quantitative viral outgrowth assay (Q-VOA) remains the gold standard at this time to provide a definitive estimate of the replication-competent proviral DNA.
- Immune-Based Strategies
This series of lectures stressed the importance of immune-based strategies to clear latently infected cells. Particularly, individuals taken off therapy will need durable protection for months or years post-treatment cessation, should there be any residual infection left. Several immune-based strategies and pathways were highlighted, including the use of broadly neutralizing antibodies, bi-specific antibodies and molecules, as well as harnessing the power of effector cells, cytotoxic T lymphocytes and regulatory pathways for immunotherapy.
- Pediatric and Early-Treatment Strategies
Dr. Debbie Persaud discussed pediatric HIV cure research, providing a conceptual framework for very early treatment towards limiting the latent HIV reservoirs. Dr. Jintanat Ananworanich gave an update on the Thai HAART vs. megaHAART study aimed at showing the effects of early HIV treatment on acute HIV infection (Fiebig stages I – IV) on both HIV reservoirs and immune function. While early treatment affects the size of the proviral DNA reservoir, it is not curative and will likely need to be combined with immune-based therapies.
- Strategies to Identify Sources of Persistent Infection: Tissue and Cellular Reservoirs
Finally, these presentations highlighted strategies to identify sources of persistent infections, such as in situ hybridization techniques, imaging of tissue reservoirs and the roles of macrophages and myeloid cells in persistent HIV infection.
Overall, there was an overwhelming consensus that the Martin Delaney Collaboratories have enabled innovative research and propelled the field forward in the last few years.
