New David Baltimore video on VIP.

[Tadeys]

New video of David Baltimore taking about VIP; but nothing new per se. Just wondering...broad neutralizing antibodies are used with VIP, so if the RIGHT BNA were used, could'nt VIP also work in theory as a therapeutic vaccine of sorts;  and since the immune system is bypassed it CAN potentially work better than the current vaccines in diffent phases, e.g.:  the vaccine on the news last week from Barcelona University’s Hospital Clinic. Any thoughts?

I think VIP was already posted on here. Just move and sorry if it is. Here is the video:http://www.huffingtonpost.com/2013/01/14/hiv-prevention-david-baltimore_n_2435387.html

[Basquo]

What is VIP?

[Tadeys]

vectored immunoprophylaxis

[Dr.Strangelove]

Haven't heard of this VIP before.
It definitively sounds promising.
Even though I hate all the marketing speak and fluffy words "VIP is a bit heroic, nobody’s ever used a vector in this way. Nobody’s ever used genes in this way." bla bla bla

But from what I understand it sounds like a gene therapy (although they don't use that term in the article): you use a viral vector to introduce new genes (in this case for the antibodies) into muscle cells. Personally, I am not yet convinced that gene therapies are safe. Sure, they have a huge potential but you never know where in your DNA the new gene is being inserted. If it's the wrong spot you have a small chance of developing a tumor. But there has been a lot going on in the field of gene therapy in recent years and perhaps these problems can be solved.

[freewillie99]

I posted this video discussing VIP about a year ago.  Good info.

http://www.youtube.com/watch?v=c4FzBC8pqDc

[freewillie99]

http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2013/01/david-baltimore-and-vectored-immunoprophylaxis.html

Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog
By Richard Jefferys, coordinator of the Michael Palm Basic Science, Vaccines & Prevention Project at the Treatment Action Group (TAG)

David Baltimore and Vectored Immunoprophylaxis

In November 2011, the laboratory of Nobel laureate David Baltimore published encouraging results from humanized mouse studies of an approach to HIV prevention they have named vectored immunoprophylaxis (assigned the slightly uncomfortable acronym VIP). The strategy involves the use of adeno-associated virus (AAV) as a vector to deliver genes that make broadly neutralizing antibodies against HIV after delivery into muscle tissue. The ultimate goal is to make an end-run around the well-documented challenges associated with designing a vaccine capable of persuading the human immune system to generate broadly neutralizing antibodies. Instead, AAV would serve as a factory for the production of these antibodies, a task to which it is thought to be well-suited because it persists for very long periods in the episome of cells (but does not integrate into the genome). The idea was first developed by Phillip Johnson at the Children’s Hospital of Philadelphia, who is collaborating with the International AIDS Vaccine Initiative (IAVI) to launch phase I human testing of an AAV encoding the broadly neutralizing antibody PG9 (listed as AAV1-PG9 on the IAVI portfolio page). Johnson’s preclinical research in the SIV/macaque model has been covered previously on the blog.

Baltimore’s VIP work is now receiving renewed attention due to the posting of a video by Cara Santa Maria, who runs the appealingly-named “Talk Nerdy to Me” science blog on Huffington Post. Inadvertently, the distillation of the research into a short video interview format suggests a narrative in which the VIP idea is unprecedented and unique, created by Baltimore and the scientists in his lab. Baltimore’s opening statement: “no one has ever tried this before,” is true in that VIP has yet to be tried in humans, but it risks rather glossing over the contributions of Johnson and many others who have long been wrestling with the complex issues involved in attempting to develop the technology for clinical testing. In essence, the approach is a gene therapy intended for healthy HIV-negative people and it is very likely—and entirely appropriate—that plans for human trials will be closely scrutinized by regulators prior to approval.

Beyond just safety, there are other issues pertaining the use of AAV as a vector that the video does not delve into. A study published in Nature Medicine in 2007 demonstrated that humans—unlike mice or monkeys—typically possess AAV-specific CD8 T cell responses that target the virus for elimination. These CD8 T cell responses are thought to have contributed to the poor performance (and in some instances, toxicity) of AAV as a gene transfer vehicle in human trials for other conditions, such as hemophilia B. The presence in humans of AAV-specific CD8 T cells may also explain why IAVI-sponsored trials of AAV as a traditional vaccine vector found that it was poorly immunogenic (only around 20% of recipients of the highest dose showed low level immune responses to the HIV antigens encoded by the AAV-based vaccine, starkly different from the promising-looking immunogenicity seen in macaques).

In their November 2011 Nature paper, David Baltimore and colleagues note that the AAV serotype they have chosen to work with, AAV8, has some differences compared to the more commonly used AAV2. They write:

"Studies in non-human primates have shown that the elicitation of capsid-specific cytotoxic T-lymphocytes is limited to AAV capsids that exhibit heparin-binding activity [26]. Interestingly, serotypes lacking heparin-binding activity, including AAV8, did not induce CTL responses, suggesting that AAV8-based vectors, like the one we have used, may circumvent previously observed immunological barriers to long-term transduction."

However, they fail to cite the 2007 paper mentioned above, which is explicit that: “alternative serotypes currently being considered for clinical applications (for example, AAV-1, AAV-8) are processed in a manner appropriate for presentation of the same epitope(s), at least by human cells, resulting in expansion of functional CD8+ T cells that are indistinguishable from those elicited by AAV-2 capsid.” 

So far it appears that the only clue as to how this might play out in humans comes from a study of a hybrid AAV vector comprising the backbone of AAV2 with an AAV8 capsid, used to deliver the gene for factor IX. In a small clinical trial for the treatment of hemophilia B in which the vector was given via peripheral vein (to target the liver), encouraging evidence of therapeutic efficacy was observed, which was not the case in a prior trial involving a vector consisting entirely of AAV2. But most participants did show some evidence of T cell responses against the AAV8 capsid, indicating that the hope that this serotype would be completely invisible to CD8 T cells has not borne out.

Thankfully though, that is not the end of the story. A study published just a couple of days ago in the journal Blood suggests that additional modifications to AAV can significantly reduce CD8 T cell recognition. And last year in the same journal, researchers reported that the AAV2 vector used to deliver the gene for factor IX in the first hemophilia B clinical trial could still be detected in muscle tissue ten years after administration. Although the level of factor IX production achieved in this trial was too low to be therapeutic, the authors conclude: “these data do establish that AAV2-mediated gene transfer to human skeletal muscle can persist for up to a decade. The use of alternate serotypes and/or delivery techniques that can perfuse muscle more extensively may improve therapeutic efficacy for this approach." This conclusion also offers hope for VIP because, as David Baltimore stresses in the video interview, his lab’s humanized mice experiments suggest that protection against HIV infection might be achievable with relatively low levels of broadly neutralizing antibodies.

[Dr.Strangelove]

Thanks for posting.

Yes, now I remember having read about this earlier.

adeno-associated virus (AAV) as a vector to deliver genes that make broadly neutralizing antibodies against HIV after delivery into muscle tissue. [...] AAV would serve as a factory for the production of these antibodies, a task to which it is thought to be well-suited because it persists for very long periods in the episome of cells (but does not integrate into the genome).

So, it's not gene therapy and my worries from the earlier post are unfounded.

Actually, it does sound pretty promising.

[YellowFever]

Hrm, so earlier attempts at using AAVs failed because our bodies have CD8 cells that can kill them. Then they found a special strain which can evade that (AAV8). So what's going to kill AAV8 once the job is done?

[freewillie99]

Nothing.  It will be start of the worldwide zombie apocalypse.