great find re: Dr Chen. Here's a little more info from that CHAVI update. I had posted these bits previously, but here it is with a few underlines.
(the bottom left is what most folks will be interested in...)
"Antibody protection from HIV-1 with in vivo passive protection trials with mabs with various specificities"
on the bottom right is Haynes recent abstract from his Seattle presentation, (where he also gave the plenary address - and discussed how microparticles from apoptotic cells alter immune response)....
In the abstract he discusses the immunosuppressive power of exposed PS :)
and- in case people have forgotten, previously he showed a picture of (Bavituximab) anti-phosphatidylserine opsonizing those microparticles :)
BTW - as a refresher- King's most recent "Duke/CHAVI/Gates" comments:
Steve King, Dec 10th 2007:
"In addition to the clinical study, we are continuing a significant amount of preclinical work in the antiviral area. Our leading collaboration is with researchers at Duke University and a number of other institutions, including Harvard. This collaboration is progressing very nicely and we are highly encouraged by the results we have seen.
As a reminder, we are exploring the potential of Bavituximab and several other anti-PS antibodies for their potential in the treatment and prevention of HIV infections. This collaboration is particularly important because without the collaboration we would not be able to conduct this informative research into the potential of our anti-PS platform for the treatment of HIV. Both we and our collaborators believe we are getting close to being able to share results of these studies either through publications or presentations in the upcoming months."
and in his previous earnings call, King's quotes were:
SK: "Our collab. with HIV researchers at Duke remains strong and is making good progress. The collab. is providing exciting, new insights into the potential of Bavi, and other Anti-PS antibodies, in HIV – data which otherwise would be extremely difficult, if not impossible, to generate. We look fwd to reporting on these results at a time our collab’s feel appropriate."
"They [Duke] are responsible for running all the studies, and aside from the cost of producing the materials, they cover all the costs of the ongoing animal studies as well as the other testing that is going on. So, while we are happy with the collaboration and are getting a lot of data from the studies they are doing, we do not necessarily have direct access to the day to day data that's being generated. It is really up to them to decide the appropriate point for updating the public. Clearly, they have an interest in this and they do have a certain amount of pressure on them as well to get the data out there. But, they're also aware that they have to be very cautious as they go out with promising data in the HIV area. So, it's our intention to continue supporting the collaboration. We do believe the data will be coming out there. "
..."So as part of that there are ongoing studies, non-human primate studies. There are add’l studies being planned.It’s a very large pgm that’s being run, again, simultaneously through these 2 different pgms – the CHAVI and then the Gates pgm [CAVD]. We are as anxious as anyone else to be able to get some of this info. out there. I know the guys at Duke will want to get it out there at the appropriate time. We are getting a lot of insight into, not just Bavi, but other antibodies that we have generated through our various collaborations."
j
January 07 CHAVI Administrators meeting-
January 07 CHAVI Administrators meeting-
MOA cytokines
Pisetsky of Duke 2005 -
Pisetsky of Duke 2006 -
Haynes and Pisetsky 2007 -
CHAVI 012, CHAVI's most recent clinical protocol -
CHAVI 012
STUDY OBJECTIVES AND DESIGN
- snip -
Measuring T and B cell responses in mucosal samples of AHI, early HIV infection, and control subjects, for study of residual immune cell activity after massive apoptosis during AHI.This is to include cytokine production, antibody production in vitro, and T cell functions in vitro. These samples will also provide material for the CHAVI effort to develop mucosal assays to monitor human vaccine clinical trials.
---------
BACKGROUND AND RATIONALE
-snip-
Innate immune responses can be activated very rapidly in response to pathogen exposure or infection, and play important roles both in containment of early pathogen replication and promotion of induction of the adaptive response. The nature of the innate response in AHI and its interaction with the adaptive response may be among the factors involved in determining the set point of plasma viremia and the preservation of central memory CD4+ T cells, two factors that have been shown to be critical metrics of disease prognosis. A key implication of this hypothesis is the suggestion that innate responses may be harnessed to form an important component of vaccine-elicited protective immunity, a setting in which rapid triggering of effector functions following exposure to HIV or HIV-infected cells is likely to be critical.
Despite the potential importance of innate responses in shaping events in primary HIV infection, little is known about the innate response at this time. One study reported transient detection of IFN-α in the serum in AHI, with levels peaking prior to the peak in acute plasma viremia, indicative of a rapid type 1 IFN response (von Sydow et al, 1991). Notably, there is a marked reduction in the number of both plasmacytoid dendritic cells (pDCs, important IFN-producing cells) and myeloid DCs (mDCs) in the blood during AHI (Pacanowski et al, 2001); whether this reflects recruitment to lymphoid tissues and/or loss is unknown. The extent of infection of DC subsets during AHI is also unclear, as is their functional capacity, although one study reported reduced costimulatory molecule expression on DCs in lymphoid tissues in AHI (Lore et al, 2002). In contrast to DCs, elevated numbers of natural killer (NK) cells are present in the blood during AHI (Alter et al, 2005), although the functions exhibited by NK cells at this time have not been characterized. Together, these studies show that innate responses are activated early in AHI, but leave many important questions about innate functions at this time unanswered. It is proposed to characterize the innate effector mechanisms activated in primary HIV infection and explore their role in control of early virus replication; and to address whether HIV impairs aspects of innate immunity in AHI to promote its persistence. This will facilitate the design of vaccination strategies to target key effector pathways and/or circumvent infection-associated impairments in innate functions.
A broad array of novel assays will be pursued and developed in the CHAVI both in support of this protocol, and through the use of the unique specimens made available by this protocol. Flow cytometric studies will identify and characterize the gut lymphocyte B cell, basophil, NK cell, T cell, dendritic, and monocyte/ macrophage populations. Immunglobulin levels will be assayed by sensitive ELISA and surface plasmon resonance assays. B and T specificities will be characterized by tetramer assays. Both microarray expression RNA analysis and proteomic profiling will be done on B and T cell populations. Mucosal antibody polyspecificity will be assessed by Luminex autoimmune antibody assays (Athena platform). Latent infection of resting T cells will be quantified by limiting- dilution assays of resting CD4 cells. Acutely expressed cytokines and apoptotic microparticles hypothesized to play a key role in AHI pathogenesis will be assayed. The CHAVI panel of cytokines including alpha IFN, TNF alpha, IL10, TGF-beta, as well as a Luminex panel of T and B regulatory cytokines, and plasma microparticles will be quantitated and as well phenotyped by flow cytometry for source of cells of origin. Plasma TRAIL, FAS Ligand and TNFRII will be determined to monitor apoptosis levels.
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