| Prospects for Eradication: Determinants of Viral Reservoirs |
TUBS1 |
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Session Room 1 |
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14:30 - 16:00, 21.07.2009 |
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TUBS1 |
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Chairs: |
Carl Dieffenbach, United States
Ben Berkhout, Netherlands
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 Session recording provided by International AIDS Society
One of the major challenges for therapeutic interventions is impacting upon the viral reservoir. This session will review the recent advances in understanding the determinants of transcriptional activity of the integrated virus and the host factors that impact of regulation of the viral life cycle revealed from new siRNA screening approaches and how these insights might provide targets for a possible therapeutic interventions that impact on the established reservoir. Current experimental therapeutic interventions for modulation of the reservoir and the prospects for eradication of the viral reservoir from the body will be reviewed.
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Presentations in this session:
14:30
TUBS101
Powerpoint | The integrated virus: determinants of transcriptional activity
Presented by Boris Peterlin, United States
| 14:50
TUBS102 | Host factors determining viral latency
Presented by David Margolis, United States
| 15:10
TUBS103
Powerpoint | Treatments to mobilize the reservoirs
Presented by Jean-Pierre Routy, Canada
| 15:30
TUBS104
Powerpoint | Is eradication a realistic aim?
Presented by Joep Lange, Netherlands
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| Powerpoints presentations |
| The integrated virus: determinants of transcriptional activity - Peterlin | |
| Treatments to mobilize the reservoirs - Routy | |
| Is eradication a realistic aim? - Lange | |
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Rapporteur reports
Track A report by Jason Brenchley
In the session on viral replication eradication M. Peterklin (UCSF) discussed the mechanisms of HIV post-integration latency. Post-integration latency is regulated by positive (P-TEFb ) and negative (NELF and DSIF) regulators of RNA transcriptional elongation. These regulators provide therapeutic targets to modulate the emergence of virus from latency. One drug (SAHA/ HMBA) in a rhesus macaque model and in PBMCs in vitro was effective in reactivating latent HIV, inhibiting other viruses (HSV, EBV, CMV, KSVH), and attenuating immune activation by increasing levels of HEXIM1/2. SAHA was as effective as T-cell activation in inducing virus replication from latent virus and thus shows much promise as a therapeutic agent. The second speaker David Margolis (UNC) discussed the efficacy of using valproic acid (an inhibitor of histone deacetylases, to induce viral replication. Valproic acid was not effective and low level viremia was persistent despite concurrent intensified ARV therapy. The third speaker, JP Routy (McGill University, Canada) discussed two prominent models of latency from the viral and cellular standpoints. Based on previously published data he discussed at least two different pools of latently infected cells, CD4 central memory and transitional memory CD4 T cells. He also found that the pool of latently infected cells, after initiation of HAART, was dependent upon nadir CD4 T cell count. He also discussed potential therapeutic interventions that might be used to decrease the size of the latently infected pool including homeostatic cytokines such as IL7, blockade of negative signaling molecules like PD1, and therapeutic vaccination to induce HIV-specific CD8 T cells. The fourth speaker, J. Lange (University of Amsterdam) discussed the hurdles that exist in the potential to eradicating the reservoir of latently infected cells. Several key obstacles involve a better understanding of the actual cells that represent the reservoir as well as a better understanding as to whether or not currently used regimens of ARVs completely shut down viral replication, especially within the gastrointestinal tract. He also presented published data clearly demonstrating that the “size” of the reservoir was significantly smaller in individuals that initiated HAART within the first 6 months of being infected and suggested that in such patients eradication of the virus might be achieved in as little as 8 years with current ARV regiments. Overall these speakers suggested that the induction of virus reactivation may have potential but eradication is not complete at this point; however, early therapy (ARV treatment during primary infection) was effective in significantly reducing the reservoir of latent virus.
Community report by Jo Watson
The holy grail in HIV viral research – eradication, was considered in this session which put a focus on the viral reservoir, and its mechanisms. HIV latent reservoirs are established early in acute HIV infection and HIV can hide in very long lived memory CD4 T cells – insensitive to the antiretroviral drugs which require viral replication. Presenters in this session described the current understandings and the challenges related to HIV persistence, as well as possible approaches for new treatment interventions. Current research includes a focus on activating latent HIV RNA particles, and directly trying to treat the HIV reservoir. Disappointing outcomes of interventions based on HAART and IL-2 have researchers now considering other approaches that can increase CD4 recovery and reduce immune activation, with potential agents such as IL-7.
But set against the science was also discussion among the presenters, including Routy from Montreal, and Lange from the Netherlands, of the risk / benefit debate as this work continues. While the “Berlin patient” was cited as an example supporting the case for continuing the focus on conducting clinical research on the reservoir, it was also questioned by Lange “whether, with advances in HIV therapy, striving for HIV eradication in more than a few specific cases, is worth the drastic interventions likely to be required to acccomplish this.” It was acknowledged that these can be potentially risky clinical interventions, and population control of HIV versus individual eradication is now a major global discussion. Nevertheless, the science for advancing immune function and for better understanding early events in primary HIV infection at tissue and organ levels continues to be a great hope.
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