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AIDS 2014: Disappointing HIV Cure News Leads to New Questions


The fourth IAS Towards an HIV Cure symposium -- an initiative of the International AIDS Society -- took place July 19-20, prior to the 20th International AIDS Conference in Melbourne.

As the symposium started, participants were still in shock as the situation with the savage attack on Malaysian Airlines flight MH17 was still fluid. IAS president Françoise Barre-Sinoussi, director of the Regulation of Retroviral Infections Division at the Institut Pasteur in Paris,dramatically opened the symposium, saying that Joep Lange -- a noted veteran AIDS researcher from the Netherlands who was killed on the flight -- believed that a cure was possible. In a mournful tone, she declared that Lange would have encouraged us to go on.

Jack Whitescarver, director of the U.S. National Institutes of Health (NIH) Office of AIDS Research, and Sharon Lewin, director of the Infectious Diseases Unit at the Alfred Hospital in Melbourne, both spoke of the importance of collaboration despite recent disappointing developments in HIV cure research. (Two weeks before the conference, researchers had announced that a child in Mississippi thought to have been cured of HIV following very early antiretroviral therapy was in fact still infected.)

Striking a hopeful tone, Whitescarver stated that the NIH is committed to increasing investment in HIV cure research over the coming years to extend the scientific advances presented at the symposium.

The dire news was not the best way to start the events in Melbourne, but nevertheless, within a few days scientific discussions at the symposium and the conference were in full swing.

As the science towards understanding an HIV cure is still new, with little data from clinical trials to present, there was not much breaking information that was newsworthy for the layperson at the symposium. But it is clear that HIV cure research is moving full steam ahead despite some complex challenges.

Jeffrey Lifson from the U.S. National Cancer Institute's Frederick National Laboratory for Cancer Research gave a keynote address reviewing those challenges and current HIV cure research approaches.

A well-known non-human primate researcher, Lifson spoke of the role of vaccines in cure research, noting the limitations of pharmacological-only approaches. He described the potential for therapeutic vaccination while laying out the specific limitations of current vaccine models. Lifson suggested that it may be possible to exploit the evolutionarily acquired wisdom of cytomegalovirus (CMV), which could tell us something about the properties of T-cell responses to CMV-vectored vaccines and its co-evolutionary relationship to HIV. Work is already in progress towards understanding this approach.

Symposium organizers chose to begin the abstract sessions with the "kill" challenge in the "shock and kill" approach currently being pursued by several research groups. The idea behind "shock and kill" is to first reactivate latent HIV in resting T-cells. Once the virus is woken up and starts replicating, it can be recognized and killed by the immune system, perhaps aided by various immune-based therapies.

Geoff Hill from the Queensland Institute of Medical Research discussed the role of allogeneic stem cell transplantation and its implications for immune control of HIV.

Researchers have learned much from past experience with "Berlin Patient" Timothy Brown -- who still appears to be cured of HIV several years after receiving bone marrow transplants from a donor with a mutation that makes immune cells resistant to infection -- as well as from 2 Boston bone marrow recipients who experienced viral remission after stopping antiretroviral therapy, but eventually experienced viral rebound. The role of graft-versus-host disease,  a condition where newly transplanted immune cells attack the body of the recipient, in the elimination of HIV in these patients is still not fully understood and there is scientific rationale for further exploration.

The rest of the first session covered several immunological possibilities for furthering the "kill" approach, all in early stages of laboratory research.

The "shock" component was discussed in the next session, devoted to further understanding the mechanisms involved in reactivating latently infected memory cells, as well as new compounds being screened for this purpose. One type of agent that has been widely studied is histone deacetylase or HDAC inhibitors. HDACs are enzymes that keep DNA tightly coiled in a cell's nucleus. HDAC inhibitors reverse this process, allowing the genetic instructions to be used to produce the proteins needed to build new cells or new virus.

Ole Schmeltz Søgaard from Aarhus University Hospital in Denmark presented findings from a clinical trial using the HDAC inhibitor romidepsin -- one of the only cure research trials presented at both the symposium and the main conference a few days later.

Romidepsin may be a more potent activator than previously studied HDAC inhibitors such as vorinostat. In this study, 3 doses of romidepsin did increase levels of cell-associated HIV RNA in CD4 T-cells as well as plasma viral load, but it still did not significantly reduce the size of the viral reservoir, according to levels of total HIV-1 DNA in CD4 cells.

One of the biggest challenges in HIV cure research is to determine the best way to measure virus reduction in the reservoir. Nicholas Chomont from the Vaccine & Gene Therapy Institute of Florida described an advance in the development of novel assays to measure HIV in the latent reservoir. TILDA (Tat/Rev Induced Limiting Dilution Assay) is a new sensitive, reproducible, quick, inexpensive test that appears promising but needs to be further analyzed.

On first hearing the news of the HIV breakthrough in the "Mississippi Baby," there was obvious sadness for the child, but there is a tremendous amount of information that can be learned from the case, and Deborah Persaud from Johns Hopkins provided a thorough update at the symposium. The child, now age 4, has restarted antiretroviral medication and remains asymptomatic.

Several nuances in the follow-up analysis provide remarkable insights into HIV pathogenesis, viral persistence, and immune control in infected babies, and further analysis is being performed on blood samples from the child. Certainly the field will move forward, and the global IMPAACT P115 trial of very early treatment of infants born to HIV-positive mothers, conducted by the NIH, is expected to proceed.

The remainder of the Towards an HIV Cure symposium was devoted to abstract sessions and roundtable discussions on other scientific and practical challenges related to cure research. Remaining scientific problems include how to effectively target other HIV reservoirs besides T-cells. Clinical trial design and ethical issues remain a subject of debate, including expansion to resource-limited settings. One of the larger issues moving forward is the need for increased funding and the hope for more public-private collaboration in the field.

The ongoing challenges will almost certainly be a big nut to crack, but if this symposium and the ongoing IAS initiative are any indication, HIV cure research is continuing. As they say, stay tuned!

Thanks to Karine Dube from the University of North Carolina for assistance with this report.