POZ Community Forums
Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: geobee on July 17, 2012, 08:34:57 pm
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A great article talking about the attempts to create synthetic prostratin. (This was the compound derived from the Somoan tree that had anti-HIV effects but was difficult to produce.) Prostratin was similar to a compound found in sea invertebrates, and it was this compound that they made a synthetic version of.
Very encouraging results were reported with a synthetic version prostratin with similar -- but more potent -- properties. Enjoy the read!
http://www.sciencedaily.com/releases/2012/07/120717141233.htm
Ooh....it gets better. Here's another link:
http://www.natap.org/2012/HIV/071612_01.htm
Heavy reading, but the last paragraph of the second link which is the doozy:
"This study is the first demonstration that designed, simplified analogues of bryostatin can serve as therapeutic leads for the eradication of HIV/AIDS. Given the problems associated with the supply of bryostatin 1 and with its side effects, this study provides a reliable synthetic source of agents that are comparable or superior to bryostatin in activity and can be tuned to accommodate clinical needs. Viral reactivation with these agents, performed in combination with HAART, would purge latent viral reservoirs while simultaneously depleting active virus. Coupling this approach with a targeted therapeutic such as an immunotoxin to more rapidly kill any resulting virus-expressing cell represents an additional therapeutic opportunity52. This type of approach, now enabled by the availability of highly potent and tunable analogues, could be used to clear all replication-competent HIV from infected individuals, thereby providing a strategy for disease eradication."
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:D very promising :D, I hope this will work and be able to see the results in the near future.
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Much work remains to get this even into a Phase I/II clinical trial. Notably, in the discussion, the following is said: "Further evaluation of these compounds in additional in vitro, ex vivo and in vivo latency induction assays is in progress." Hopefully, the compounds will show efficacy in ex vivo patient samples from HAART-suppressed patients. :)
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I remember reading about prostratin last year and it's potential antiviral properties. I knew they had developed a synthesized form, but hadn't heard much about it since. The more curative research and development, the better.
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Very interesting study. Thank you for posting :).
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I remember reading about prostratin last year and it's potential antiviral properties. I knew they had developed a synthesized form, but hadn't heard much about it since. The more curative research and development, the better.
Prostratin and bryologues come from a kind of tree in Samoa and a kind of sea invertebrates respectively and they are difficult to obtain in mass quantity, even for research purpose. Now chemists know how to synthesize them in lab economically in large quantities. Thanks to all researchers, clinicians, chemists for their collaborative efforts! ;)
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Evaluation of Different CD4 T-Cell Reservoirs
Written by Alain Lafeuillade
Wednesday, 08 February 2012 13:03
Evaluation of Different CD4 T-Cell Reservoirs
A new model allowing the evaluation of many primary CD4 T-cell reservoirs is described. It shows potentially important differences within the latently infected cell pools and looks promising for the in vitro testing of different agents aimed at reactivating HIV from latency.
The study of HIV latency has been generally hindered by the lack of a robust and rapidly deployable cell model that involves primary human CD4 T lymphocytes.
Current primary lymphocyte models more closely reflect the in vivo state of HIV latency and may not reflect the heterogeneous nature of the latent reservoir.
Even studying latently infected cells from HIV-infected subjects is challenging. These cells are very rare in the blood, and there are no methods to enrich them.
Immortalized T-cell lines have improved our understanding of HIV latency but they do not recapitulate the non-dividing G0 state of resting CD4 T cells in vivo.
Most primary cell models often takes several weeks or months of continuous culture to get sufficient latently infected non-dividing T cells.
They are, therefore unappropriate for large-scale screening for agents that could reactivate and eliminate latent proviruses.
Furthermore, it is now demonstrated that the latent reservoir in vivo might be more complex than previously thought. It involves both central memory T cells that typically harbor a larger proportion of the latent proviruses, but also transitional memory cells that appear to live longer and to be continually renewed by cytokine-induced homeostatic proliferation.
In this paper (1) Warner Greene laboratory adapated the model previously described by Una O'Doherty laboratory (2) to make it more dynamic and suitable for drug screening. This model is more rapid (viral proteins can be detecetd in latently infected cells within 2 hours after induction) and allows the quantification of the release and accumulation of viral particles after reactivation.
This model may also be useful for further characterizing the subset of latently infected cells that fail to respond to classic reactivation signals to discern the underlying mechanism(s).
The authors tested the effects of Prostratin (NF-kB stimulator), HDAC inhibitors (valproic acid, SAHA, TSA), HMBA (p-TEFB activator) and different combinations of these drugs in their model.
Interestingly, they found that transcriptional activators failed to synergize with chromatin-modifying agents. Unlike prostratin alone, the effects of the synergies were not consistent among different donors. each HDAC inhibitor was screened in combination with HMBA. Again, only modest, transient synergy was observed with any of the combinations.
When they addressed the reactivation of different parts of the reservoir, they found that transitional memory cells may be more susceptible to certain inducers. Transitional memory cells were significantly more susceptible to reactivation with PMA+ ionomycin, anti-CD3+anti-CD28 antibodies, and prostratin, although central memory cells and transitional memory cells exhibited similar levels of reactivation with IL-7.
These data also suggest that the chromatin environment might have a more significant role in establishing latency in proliferating cell lines than in quiescent primary CD4 T cells.
References
1-Lassen KG, et al. A Flexible Model of HIV-1 Latency Permitting Evaluation of Many Primary CD4 T-Cell Reservoirs. PLoS One. 2012; 7(1): e30176. Epub 2012 Jan 24.
2-Swiggard WJ,et al. Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. J Virol 2005; 79: 14179–14188