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Author Topic: Chemists Synthesize "Bryologs" That Flush out Latent HIV  (Read 2656 times)

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Offline geobee

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  • Posts: 288
Chemists Synthesize "Bryologs" That Flush out Latent HIV
« on: July 17, 2012, 08:34:57 PM »
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."

« Last Edit: July 18, 2012, 01:35:27 AM by geobee »

Offline younghopefulpoz

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  • Posts: 55
Re: Chemists Synthesize "Bryologs" That Flush out Latent HIV
« Reply #1 on: July 18, 2012, 11:08:53 AM »
:D very promising :D, I hope this will work and be able to see the results in the near future.

Offline vaguesbleues

  • Member
  • Posts: 93
Re: Chemists Synthesize "Bryologs" That Flush out Latent HIV
« Reply #2 on: July 18, 2012, 02:52:37 PM »
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.  :)
03/10/2011 - Tested HIV negative
04/26/2011 - Inconclusive WB result
05/19/2011 - Confirmed HIV positive
                    VL < 50, T-Cell 747 (30%)
06/13/2011 - VL 345, T-Cell 841 (30%)
08/23/2011 - VL 50,100, T-Cell 1155 (19%) - CMV
09/18/2011 - Started Atripla!!
11/07/2011 - VL 489, T-Cell 881 (31%)
02/08/2012 - VL Undetectable!!, T-Cell 772 (34%)
08/08/2012 - VL UD, T-Cell 1070 (42%)
11/05/2012 - VL UD, T-Cell 1174 (35%)
03/18/2013 - VL UD, T-Cell 972 (28%)
10/04/2013 - VL UD, T-Cell 1025 (34%)

Offline dpb

  • Member
  • Posts: 89
Re: Chemists Synthesize "Bryologs" That Flush out Latent HIV
« Reply #3 on: July 18, 2012, 06:05:04 PM »
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.
Date        CD4    %    VL
1/15/11    Diagnosed
3/1/11    525    18    168,518
5/12/11    558    16    331,791
5/16/11    Started Atripla
5/31/11    NA    NA    1,200
6/15/11    721    21    330
7/15/11    649    23    231
8/15/11    569    25    UD
11/17/11  752    26    UD
3/1/12    634    27    UD
7/2/12    594    26    UD
2/13       676    30    UD
9/13       662    31    UD

Offline Andygt

  • Member
  • Posts: 3
Re: Chemists Synthesize "Bryologs" That Flush out Latent HIV
« Reply #4 on: July 21, 2012, 03:37:10 PM »
Very interesting study. Thank you for posting :).

Offline hopeisvague

  • Member
  • Posts: 11
Re: Chemists Synthesize "Bryologs" That Flush out Latent HIV
« Reply #5 on: July 22, 2012, 02:16:55 PM »
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! ;)
201206 351/95000 Started I/T

Offline Mishma

  • Member
  • Posts: 190
    • Marquis de Vauban
Re: Chemists Synthesize "Bryologs" That Flush out Latent HIV
« Reply #6 on: July 22, 2012, 06:46:55 PM »
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: 1417914188
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

 


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