Dear HOPEians,
Thank you for attending the HOPE Collaboratory-Wide Meeting on Nov 27, 2023. Below is a summary of the meeting, actions, and announcements.
RF1: Ulrike Lange
Ulrike gave updates on investigating HIV-1 proviral integration site-driven proliferation dynamics in vitro. She shared data on the expansion dynamics of HIV-1 infected CD4+ T cells and how integration site can potentially drive transcription of nearby genes, including those related to cell cycle. Ulrike shared data on the LTR cis elements as one mechanism for IS-driven expansion. The hypothesis is transcriptional activity of proviruses impacts on transcriptional activity of integration genes, which promotes cell survival/proliferation. Going forward, they are looking at in vitro selection models, workflow for integration site sequencing and clonality assessment, clonal expansion of transduced cells, qualitative evaluation of data, biological replicates and assess the effect of modulation of proviral transcriptional activity.
Shared papers:
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“Specific HIV integration sites are linked to clonal expansion and persistence of infected cells”
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“HIV proviral DNA integration can drive T cell growth ex vivo”
Community: Patricia Defechereux
Patricia shared some upcoming events with World AIDS Day (more information to come). HOPE is hosting an Instagram live “Ask an HIV Cure Scientist” and feature some of Paul Edmond’s art display at Gladstone Institutes. Patricia is working on data analysis from the focus groups. In Brazil, Marco is leading efforts to connect with other institutions and communities to develop cure awareness activities as well as discuss identity post-cure with an upcoming stakeholder meeting. We are currently planning future events in NYC, Oakland, and Munich including the IAS Global Village. Another video project is underway, with the collaboration of the Last Gift Cohort and Sara Gianella. Additionally, updates have been made to the journal language for publication (ARHR).
RF2: Matt Parsons / Susana Valente
Matt Parsons gave an update on a non-human primate spironolactone dose study. They currently have three rhesus macaques getting daily oral doses of SP. After looking at PK analysis the animal study is done as well as the blood chemistries and LCMS data. Their next steps are to send shipments of NHP specimens to Valente lab, examine the western blots for XPB degradation, collect PBMC in normal EDTA and transcriptomics.
Susana shared RhM study comparison with the PK results of the UW-Madison collaboration and AFRIMS collaboration. There was an increase in differentially expressed genes with increasing doses of SP. Unlike in higher doses, there was no significant enrichment of inflammation-related gene pathways among differentially expressed genes with 24 mg/kg/day. Genes involved in translation are upregulated with SP treatment.
RF3: Melanie Ott / Priti Kumar / Niren Murthy
Melanie shared updates on their gene editing project. After attending the FDA advisory board meeting on the use of CRISPR with sickle cell anemia, she learned that CRISPR Therapeutics Announces Completion of FDA Advisory Committee Meeting for Exagamglogene Autotemcel (exa-cel) for Severe Sickle Cell Disease. The CRISPR treatment ex vivo targets the repressor of hemoglobin genes and has proven to cure sickle cell anemia. The panel was supportive of CRISPR treatment in human patients. The next steps will be cyclinT editing by Priti’s group. We will pursue two strategies – ex vivo treatment and injection into humanized mice, and use LNPs to test both ex vivo engineering injection and direct injection of LNP base editing.
Priti shared that the prime editing approach and enzyme are large. The larger the payload is, the harder it is to package. We will incorporate mRNA and put it in hematopoietic stem cells. Niren has done two rounds of transfection and in vivo is ideal. Double-edited hematopoietic stem cells could be achievable, but there is a worry about prime editing in preclinical models.
Announcements
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Dec 1st is World AIDS Day, join HOPE and Gladstone events!
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SAVE the DATE– HOPE Annual Meeting will be held in NYC on Sept 30-Oct 1, 2024
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The Progress Report process will begin soon.
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Check out the Community Jam Board to help address some of our community’s concerns
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The next RF meetings: Please come prepared with some updates.
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RF1 Dec 18
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RF2 Dec 13
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RF3 Dec 4
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Upcoming HOPE Guest Speakers:
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Feb 26 Michael Emerman
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Apr 22 Ivan D’Orso
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May 20 Alex Marson
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Jun 24 Mohamed Abdel-Mohsen
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Please Acknowledge HOPE & the NIH in any publications or presentations and notify the Program Manager. Here are some examples of what you can include.
“Research reported in this publication was supported by the NIAID of the National Institutes of Health under award number UM1AI164559, with co-funding support from NIDA, NIMH, NHLBI, the NIDDK, and the NINDS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.”