HIV Aids - The evidence comes together, and the Perth Group is correct.

Author

The evidence comes together, and the Perth Group is correct.

monty1945@lycos.com

2006-07-29, 9:19 pm

Today on sciencedaily.com
(http://www.sciencedaily.com/release...60727181314.htm):

"In the July 28 issue of Cell, the USC-Harvard group shows that the
protein Nuclear Factor of Activated T cells (NFAT), in collaboration
with FOXP3, an essential factor in regulatory T cells, orchestrates a
genetic program critical to immune tolerance.

But the same NFAT, paired with a second family of proteins known as
AP-1, instead stimulates immune response."

When you combine this finding with the following studies, it is clear
that there is a redox situation that favors what is generally
considered "immunosuppression" in the "HIV/AIDS" context:

J Immunol. 1996 Jul 1;157(1):160-9.

Sublethal levels of oxidative stress stimulate transcriptional
activation of c-jun and suppress IL-2 promoter activation in Jurkat T
cells.

Beiqing L, Chen M, Whisler RL.

Department of Medical Biochemistry, William H. Davis Medical Research
Center, Ohio State University, Columbus 43210, USA.

Sublethal levels of oxidative stress are well known to alter T cell
functional responses, but the underlying mechanisms are unknown. The
current study examined the effects of oxidative stress on
transcriptional activities mediated by c-Fos/c-Jun AP-1 and the nuclear
factor of activated T cells (NF-AT). The present results show that
Jurkat T cells acutely exposed to micromolar concentrations of H2O2
exhibit substantial increases in AP-1 binding activity and the
expression of c-jun but not c-fos mRNA. The preferential induction of
c-jun by H2O2 did not represent redox stabilization of mRNA
transcripts, and oxidative signals closely resembled PHA/PMA
stimulation by effectively transactivating the full length c-jun
promoter via the proximal jun1 tumor promoter-responsive element
(TRE)-like promoter element. Similarly, the complexes binding the
consensus AP-1 TRE and jun TRE-like motifs in cells exposed to
oxidative signals or PHA/PMA were indistinguishable, being composed of
c-Fos, c-Jun, and JunD. However, PHA/PMA but not oxidative signals
induced the coordinate activation of reporter constructs containing the
AP-1-TRE, NF-AT, and IL-2 promoter regions along with IL-2 mRNA
expression. Furthermore, sublethal levels of H2O2 actively suppressed
the transcriptional activation of NF-AT and IL-2 reporters as well as
the expression of IL-2 mRNA in cells stimulated with PHA/PMA. Gel shift
analysis revealed that oxidative suppression of NF-AT represented
inhibition in the early generation of NFAT complexes rather than the
binding of preformed NF-AT complexes. These results suggest that
oxidative signals can positively and negatively regulate T cell
transcriptional events and that changes in cellular redox can uncouple
AP-1 regulation of c-jun from transcriptional up-regulation of IL-2 via
NF-AT.

And:

Cell Immunol. 1997 Jan 10;175(1):41-50.
Impaired induction of c-fos/c-jun genes and of transcriptional
regulatory proteins binding distinct c-fos/c-jun promoter elements in
activated human T cells during aging.Whisler RL, Chen M, Beiqing L,
Carle KW.
Department of Medical Biochemistry, The William H. Davis Medical
Research Center, The Ohio State University, Columbus 43210-1228, USA.

The activation of transcriptional factor c-Fos/c-Jun AP-1 is essential
for normal T cell responsiveness and is often impaired in T cells
during aging. In the present study, we investigated whether aberrancies
in the regulation of c-fos/c-jun at the mRNA or protein level might
underlie the age-associated impairments of AP-1 in human T cells.
Whereas T cells from young subjects stimulated with cross-linked
anti-CD3epsilon mAb OKT3 plus PMA or with the lectin PHA plus PMA
demonstrated considerable increases in c-Fos protein expression, the
expression of c-Fos but not c-Jun was markedly reduced in stimulated T
cells from certain elderly subjects. In addition, RNase protection
assays revealed that anti-CD3/PMA-stimulated T cells from a substantial
proportion of elderly subjects exhibited decreased levels of c-fos
and/or c-jun mRNA compared to T cells from young subjects. Using
electrophoretic mobility shift assays, the levels of nuclear regulatory
proteins recognizing the AP-1 consensus TRE motif, the proximal c-jun
TRE-like promoter element, and the c-fos serum response element (SRE)
were determined in resting and stimulated T cells. Although the
stimulation of T cells from young subjects resulted in coordinated
increases of nuclear protein complexes binding the AP-1 TRE, c-jun TRE,
and c-fos SRE DNA sequence motifs, age-related reductions in the
activation of AP-1 were accompanied by decreased levels of c-jun TRE
and c-fos SRE binding complexes. Furthermore, the nuclear protein
complexes binding the SRE motif induced in activated T cells of young
and elderly subjects contained serum response factor and Elk-1 pointing
toward age-related defects in the activation of transcriptional
regulatory proteins distinct from c-jun/AP-1. These results suggest
that underlying aberrancies in the induction of c-fos/c-jun as well as
their nuclear regulatory proteins may contribute to the age-related
impairments of AP-1 activation in human T cells.

PMID: 9015187 [PubMed - indexed for MEDLINE]

There were posters on this NG not long ago who talked of "Tregs" being
the causative factor, but what they did not consider is that the
"Tregs" just don't "go bad" for no reason - particular stressors are
the underlying cause.

monty1945@lycos.com

2006-07-29, 9:19 pm

Another one:

Cell Immunol. 1996 May 1;169(2):185-95.
Age-related decreases in IL-2 production by human T cells are
associated with impaired activation of nuclear transcriptional factors
AP-1 and NF-AT.Whisler RL, Beiqing L, Chen M.
Department of Medical Biochemistry, William H. Davis Medical Research
Center, Ohio State University, Columbus 43210-1228, USA.

Although transcriptional factors AP-1 and nuclear factor of activated T
cells (NF-AT) are important for the normal induction of IL-2, it is
unknown if the age-related decline in IL-2 production by activated
human T cells may be associated with aberrancies in transcriptional
regulatory proteins. In the current studies, IL-2 production by T cells
from elderly (mean 78 years) and young (mean 37 years) humans was
measured in cultures stimulated with PHA, PHA plus PMA, crosslinked
anti-CD3 mAB OKT3 plus PMA, or PMA plus ionomycin. Substantial
decreases of IL-2 production were observed for cell cultures from 7 of
12 elderly individuals in response to the different stimuli, whereas
the levels of IL-2 produced by stimulated T cells from other elderly
individuals were equivalent to those observed for stimulated T cells of
young subjects. Analyses of nuclear extracts by electrophoretic DNA
mobility shift assays showed that decreased IL-2 production by
stimulated T cells of elderly individuals was closely associated with
impairments in the activation of both AP-1 and NF-AT. By contrast, T
cells from elderly subjects with normal levels of IL-2 production
exhibited normal activation of AP-1 and NF-AT. In addition, the results
of competition experiments analyzing the normal components of NF-AT
showed that the age-related reductions in stimulus-dependent NF-AT
complexes corresponded to the slow migrating complexes that were
composed of c-Fos/c-Jun AP-1. The resting and stimulated levels of NF
kappa B were reduced in T cells from certain elderly individuals;
however, alterations of NF kappa B did not correlate with changes in
IL-2 expression. Thus, these results show that age-related impairments
in the activation of AP-1 and NF-AT are closely associated with
decreased expression of IL-2 and further suggest that aberrancies in
the signaling pathways important for the induction of transcriptionally
active c-Fos/c-Jun AP-1 may contribute to the impaired activation of
NF-AT.

GMCarter

2006-07-29, 9:19 pm

On 29 Jul 2006 15:19:03 -0700, monty1945@lycos.com wrote:

>Today on sciencedaily.com
>(http://www.sciencedaily.com/release...60727181314.htm):
>
> "In the July 28 issue of Cell, the USC-Harvard group shows that the
>protein Nuclear Factor of Activated T cells (NFAT), in collaboration
>with FOXP3, an essential factor in regulatory T cells, orchestrates a
>genetic program critical to immune tolerance.
>
>But the same NFAT, paired with a second family of proteins known as
>AP-1, instead stimulates immune response."
>
>When you combine this finding with the following studies, it is clear
>that there is a redox situation that favors what is generally
>considered "immunosuppression" in the "HIV/AIDS" context:
>
>J Immunol. 1996 Jul 1;157(1):160-9.
>
>
>Sublethal levels of oxidative stress stimulate transcriptional
>activation of c-jun and suppress IL-2 promoter activation in Jurkat T
>cells.

Ah...yeah--and to the extent that oxidative stress is a part of HIV
infection, this observation leads to some therapeutic implications.

But OS does not cause CD4 counts to decline.

Do you know the role of NF-kB in HIV disease?

I am quite certain you haven't a clue what any of these abstracts
mean. Though they are certainly interesting!

George M. Carter

Chris Noble

2006-07-30, 2:19 am

monty1945@lycos.com wrote:
> Another one:
>
> Cell Immunol. 1996 May 1;169(2):185-95.
> Age-related decreases in IL-2 production by human T cells are
> associated with impaired activation of nuclear transcriptional factors
> AP-1 and NF-AT.Whisler RL, Beiqing L, Chen M.
> Department of Medical Biochemistry, William H. Davis Medical Research
> Center, Ohio State University, Columbus 43210-1228, USA.
>
> Although transcriptional factors AP-1 and nuclear factor of activated T
> cells (NF-AT) are important for the normal induction of IL-2, it is
> unknown if the age-related decline in IL-2 production by activated
> human T cells may be associated with aberrancies in transcriptional
> regulatory proteins. In the current studies, IL-2 production by T cells
> from elderly (mean 78 years) and young (mean 37 years) humans was
> measured in cultures stimulated with PHA, PHA plus PMA, crosslinked
> anti-CD3 mAB OKT3 plus PMA, or PMA plus ionomycin. Substantial
> decreases of IL-2 production were observed for cell cultures from 7 of
> 12 elderly individuals in response to the different stimuli, whereas
> the levels of IL-2 produced by stimulated T cells from other elderly
> individuals were equivalent to those observed for stimulated T cells of
> young subjects. Analyses of nuclear extracts by electrophoretic DNA
> mobility shift assays showed that decreased IL-2 production by
> stimulated T cells of elderly individuals was closely associated with
> impairments in the activation of both AP-1 and NF-AT. By contrast, T
> cells from elderly subjects with normal levels of IL-2 production
> exhibited normal activation of AP-1 and NF-AT. In addition, the results
> of competition experiments analyzing the normal components of NF-AT
> showed that the age-related reductions in stimulus-dependent NF-AT
> complexes corresponded to the slow migrating complexes that were
> composed of c-Fos/c-Jun AP-1. The resting and stimulated levels of NF
> kappa B were reduced in T cells from certain elderly individuals;
> however, alterations of NF kappa B did not correlate with changes in
> IL-2 expression. Thus, these results show that age-related impairments
> in the activation of AP-1 and NF-AT are closely associated with
> decreased expression of IL-2 and further suggest that aberrancies in
> the signaling pathways important for the induction of transcriptionally
> active c-Fos/c-Jun AP-1 may contribute to the impaired activation of
> NF-AT.

So I take it you have emailed the authors of these studies to ask them:
a) whether they have heard of the Perth Group
b) whether they think their papers support the claims of the Perth
Group
c) whether they think you have any idea whatsoever about virology

My guess would be - No, No and No! But go ahead. Prove me wrong. Email
them.

Chris Noble