Act Acting » Acting Agents » About that development…

About that development…

Question:

Hi,   Just a thought – some claimed that there’re still virus being produced under HAART but they’re "weakened" or less "fit". So my question is, if a patient is doing well clinically on some combo but not showing reduciton on standard VL nor on this new test, is it still a good idea to change combo? How can you know if a virus is "fit" or not?

Currently the only way would be to try to isolate and analyse viral clones for resistance mutations, ability to culture it etc etc.  Not entirely reliable, since the virus would quickly revert to a slightly different strain once removed from the host.  As Dave said. hopefully this new test will show whether anything of note is actually happening. One caveat though: it’s been known for some time that the viral proteins themselves are capable of causing cellular dysfunction: maybe non-infectious virus would still be enough to cause disease or allow progression?  After all, the ratio of infectious to non-infectious virus in the _untreated_ infection is something like 1:60,000  Ouch.  (That’s peripherally though, bear in mind that the real problem is probably in the lymph nodes). If a patient is clinically well, but with a high viral load, there’s not a lot to distinguish someone with a failed combo but just not yet ill (like the clinical latency seen in untreated infections) or a semi-working combo where the PI’s are sitting on the virus.  In the latter situation there’s no guarantee that the drugs are working effectively (after all, the dosing is designed for combo therapy) and I might argue that in fact they _aren’t_, since we have this virion production leading to the viral load.  RTI’s do not affect virion production from provirus either, so these new virions appearing as viral load are probably from an increase in the trickle of infective events known to occur even under HAART. Cheers Bennett — Big fish, little fish, put it in a box.  Stacking boxes, stacking boxes… ICQ: 14197406 (swap cam for spam to reply via email)

Response:

Hi,   Just a thought – some claimed that there’re still virus being produced under HAART but they’re "weakened" or less "fit". So my question is, if a patient is doing well clinically on some combo but not showing reduciton on standard VL nor on this new test, is it still a good idea to change combo? How can you know if a virus is "fit" or not?

   If this test measures actual infections, it will show if the produced virus if fit in terms of it’s ability to perpetuate the infection.    If the RTI drugs are not working (more provirus is created by insertion of HIV DNA into the human genome) and the PI drugs are working (gag is not cut to pieces and reformed into working viral capsids) this new test shows how really effective the cocktail is working. What is the question?       Gertrude Stein’s last words No one mouth is big enough to utter the whole thing.    Alan Watts On Display in the UK     http://www.webgallery.connectfree.co.uk

Response:

  Did you read anything on the technique that the test used?  It would seem cumbersome to test infectivity by counting the number of actual infections.

Just read the abstract for the first time: can’t get to the fulltext at the moment.  As I suspected they’re looking for the circular cDNA products of reverse-transcription, which occurs just after infection.  They don’t say if they quantitated anything, but I think they’re simply trying to find PCR products.  It’d be easy to do: create primers that bind to the LTR but lead _away_ from the viral genome.  You’d only get a product if the genome was circular, i.e. one of these RT products.    If the test somehow used surrogate measurements like quantifying gag or counted viral errors know to result in non infective virus there might be something to the hype.

Not sure what you’re getting at here (maybe it’s cos I haven’t had breakfast yet!).  This test detects ongoing successful replication: if that is inhibited in any way this measurement will fail.  Pretty clever, elegantly simple, very powerful – just like molecular biology used to be… :o )  This isn’t a surrogate marker, this is direct evidence of successful viral replication: in the era of PI’s not even viral load can boast that, nor can anything else for that matter.  What they’ve done is put it together with recent work showing the proviral load to be persistant and slowly decaying in some people, and suggest that proviral decay _might_ still be possible providing we have absolute evidence of viral shut-down.  Viral load cannot do that, this new test can.  Put people on the right therapy and maybe it’ll fade away.  I’m not holding my breath just yet though… In a few days I’ll be in a lab again: I’ll read through the article proper and get back. Cheers Bennett — Big fish, little fish, put it in a box.  Stacking boxes, stacking boxes… ICQ: 14197406 (swap cam for spam to reply via email)

Response:

Hi,    Just a thought – some claimed that there’re still virus being produced under HAART but they’re "weakened" or less "fit". So my question is, if a patient is doing well clinically on some combo but not showing reduciton on standard VL nor on this new test, is it still a good idea to change combo? How can you know if a virus is "fit" or not? – Hide quoted text — Show quoted text –   Did you read anything on the technique that the test used?  It would seem cumbersome to test infectivity by counting the number of actual infections. Just read the abstract for the first time: can’t get to the fulltext at the moment.  As I suspected they’re looking for the circular cDNA products of reverse-transcription, which occurs just after infection.  They don’t say if they quantitated anything, but I think they’re simply trying to find PCR products.  It’d be easy to do: create primers that bind to the LTR but lead _away_ from the viral genome.  You’d only get a product if the genome was circular, i.e. one of these RT products.    If the test somehow used surrogate measurements like quantifying gag or counted viral errors know to result in non infective virus there might be something to the hype. Not sure what you’re getting at here (maybe it’s cos I haven’t had breakfast yet!).  This test detects ongoing successful replication: if that is inhibited in any way this measurement will fail.  Pretty clever, elegantly simple, very powerful – just like molecular biology used to be… :o ) This isn’t a surrogate marker, this is direct evidence of successful viral replication: in the era of PI’s not even viral load can boast that, nor can anything else for that matter.  What they’ve done is put it together with recent work showing the proviral load to be persistant and slowly decaying in some people, and suggest that proviral decay _might_ still be possible providing we have absolute evidence of viral shut-down.  Viral load cannot do that, this new test can.  Put people on the right therapy and maybe it’ll fade away.  I’m not holding my breath just yet though… In a few days I’ll be in a lab again: I’ll read through the article proper and get back. Cheers Bennett — Big fish, little fish, put it in a box.  Stacking boxes, stacking boxes… ICQ: 14197406 (swap cam for spam to reply via email)

Before you buy.

Response:

writes: Now, this cannot be differentiated by viral load tests: provirus will produce virions which may not be infectious, but may still be detected by viral load tests.  The new test measures successful _replication_ of the virus: if I recall correctly, these circles are by-products of reverse-transcription.  That requires successful infection, not just production of virions from pre-existing provirus.  As such, levels will drop with every form of therapy, current and new.  Not so RNA viral load… Integrase inhibitors won’t result in a build-up of these circles, because they are not integrated anyway, only the linear DNA genomes are integrated. Anyway, that was my take on the discovery, FWIW.

   Did you read anything on the technique that the test used?  It would seem cumbersome to test infectivity by counting the number of actual infections.       If the test somehow used surrogate measurements like quantifying gag or counted viral errors know to result in non infective virus there might be something to the hype. What is the question?       Gertrude Stein’s last words No one mouth is big enough to utter the whole thing.    Alan Watts On Display in the UK     http://www.webgallery.connectfree.co.uk

Response:

UK Blood Test May Transform HIV Treatment – Papers Updated 7:56 PM ET December 27, 1999 LONDON (Reuters) – British scientists have developed a blood test which may transform HIV treatment around the world and end up saving millions of lives, newspapers reported on Tuesday. They said the test, developed by a team led by Dr Sunil Shaunak at London’s Hammersmith hospital, could tell doctors when the AIDS virus was hiding in the body.

<snip I read this in the Times a few days ago.  "Could save Millions" they say. Hmmm.  A lot of hype methinks, but a day later I twigged on a real use of the test. In terms of therapy we already know that viral load can predict time to AIDS and clinical benefit from therapy.  However, you may remember a case presented here a few months back (by Franmerk I think, but it may have been someone else) of someone on HAART with "treatment failure", ie a highish viral load.  Genetic analysis showed that the virus was still sensitive to the protease inhibitor in the cocktail.  The question eventually arose: was viral load meaningful in this situation?  The virus, while containing RNA, wouldn’t be infectious if the PI was still working…. Now, this cannot be differentiated by viral load tests: provirus will produce virions which may not be infectious, but may still be detected by viral load tests.  The new test measures successful _replication_ of the virus: if I recall correctly, these circles are by-products of reverse-transcription.  That requires successful infection, not just production of virions from pre-existing provirus.  As such, levels will drop with every form of therapy, current and new.  Not so RNA viral load… Integrase inhibitors won’t result in a build-up of these circles, because they are not integrated anyway, only the linear DNA genomes are integrated. Anyway, that was my take on the discovery, FWIW. Cheers Bennett

Response:

blood is well-known. A test to tell you when the AIDS virus [is] hiding in the body doesnt offer anything new in terms of understanding viral replication during treatment. My thoughts also when I read most reporting on new med’s of any kind, the press seems to just regurgitate the PR folks press releases….

Frank, Gary – I think the reason for the high hopes (and hypes) is that with the new test antivirals can be evaluated for HIV suppression not only in the blood, but IN GENERAL…lymph nodes and ‘resivoirs’ included;  leading to more effective treatment. Trying to fine-tune the picture on a TV set while listening only to the sound is somewhat usefull, but at some point to make further progress and reach your goal, you actually NEED to be looking at the real thing you are trying to affect. It may well be that some less toxic and/or more effective agents (with respect to overall HIV replication) have been tested in humans already, but were dropped after pilot studies showed standard blood VL tests that were not quite as suppressive as others that were moved forward. But what if the peripheral blood VL is a related but still secondary ’shadow’ of the real viral production (as in fact it is)?  And what if some ignored or new compounds turn out to actually lower the true OVERALL replication rate, as measured by the new test, while not being as rapidly suppressive to the peripheral blood VL?   So what if the PBL-VL measurement does not go down as fast?  It’s just a shadow anyway. Knowing this, such compounds WOULD probably be promoted to further longer-term human testing.  It may well be the case that in the long run, they would have a more profound and more durable effect, since they are acting on the REAL culprit: replication in lymph nodes and resivoirs. Now that there’s a way to tell what’s really happening, hopefully they can come up with truly effective and durable anti-virals much more rapidly. That DOES justify a pretty high level of importance, IMHO.

Response:

– Hide quoted text — Show quoted text – UK Blood Test May Transform HIV Treatment – Papers Updated 7:56 PM ET December 27, 1999 LONDON (Reuters) – British scientists have developed a blood test which may transform HIV treatment around the world and end up saving millions of lives, newspapers reported on Tuesday. They said the test, developed by a team led by Dr Sunil Shaunak at London’s Hammersmith hospital, could tell doctors when the AIDS virus was hiding in the body. Here

Related Posts

Leave a Reply