The Heart of the Firestorm

Charles P. McCarthy pandoc at ix.netcom.com
Mon Nov 11 19:51:52 EST 1996


The Heart of the Firestorm

Activation, Anergy, and Apoptosis -gp120 and IL-2

Liegler and Stites demonstrated the in vitro restoration of
proliferation in CD4+ T-lymphocytes by IL-2  following anergy
induction via HIV glycoprotein 120 (gp120) .  If this type of
restoration is not seen in patients with advanced HIV disease
following in vivo infusions of IL-2 it is because of high 
levels of viral antigen .  

In filariasis we see this same phenomenon of increasing anergy 
proportionate to the levels of parasite antigens.  In the case 
of HIV infection, the effect, extent and duration of IL-2 
proliferation restoration would be determined by the amount of 
gp120 being secreted in vivo. 

HIV gp120 not only provides the molecular basis of aberrant
activation and anergy, due to its dual properties of CD4 binding 
and MHC mimicry, but also its membrane interactions with CD4, 
transglutaminase, etc. are the molecular basis for apoptosis in 
HIV infection.  

Cohen et al demonstrated the markers that can be used to
differentiate between physiological apoptosis and the mitotic 
chaos that occurs in HIV infection.

The pathology of AIDS is the sequelae that results from the
secretion of gp120 by host cells infected with HIV and the
interaction of this glycoprotein with target cells.  

Abnormal flux of Ca++ into intracellular compartments resulting
from gp120/host membrane interactions, is a fundamental ionic
signal to all messenger molecules.  It propagates the aberrant 
lipid metabolism that supports viral assembly and budding while 
infected cells rapidly burn to the ground.  The glowing gp120 
embers from the firestorm drive uninfected immune cells to a 
fiery, premature death. 

Endogenous or exogenous agents that directly or indirectly 
reduce gp120 secretion, compete effectively with its binding 
sites, or reduce its passage through host cell membranes, will
produce sustainable therapeutic advances.  To the degree that 
they are sustained by interventions that may be circumvented 
by mutation and selection, they will be relatively short-lived.

Saturating doses of natural, small molecule, metabolic 
immunomodulators appears to be the treatment of choice.

Any and all researchers with g.c. facilities please 
inquire via email for current priorities in isolation 
and identification.  Thank you.

"Life is a membrane that reproduces."
                         Pandoc

Charles P. McCarthy, Clinical Specialist
Healthcare Consulting and
   Medical Research
Professor Emeritus of Pantherapeuticological Medicine
Carmichael, CA USA

Cohen DI; Hartmann DP; Donoghue E; Raffeld M
A central mechanism of HIV-mediated apoptosis.
Laboratory of Immunoregulation, NIAID, Bethesda, MD.
Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;
150.

Abstract: 

Although it has been widely proposed that apoptosis or
programmed cell death (PCD) plays a central role in HIV- mediated
T cell killing, no previous report has linked this observation to a
defined cellular mechanism explaining the cell death. We have
previously established that the HIV- initiated form of PCD
differs from most common forms of T cell developmental PCD
insofar as tyrosine kinases play a central role in initiating the
HIV-mediated process (Cohen et al., Science 256, 542, 1992). We
show here that single cell killing either during infection of
PBLs with ex vivo clinical HIV isolates or during co-culture of
cells transfected to express HIV envelope glycoproteins occurs
because cells are lethally arrested at the G2/M cell cycle
interface and undergo a death process termed mitotic catastrophe.
Cells dying of HIV-mediated apoptosis overaccumulate activated
forms of two mitotic regulators, cyclin B and p34cdc2 kinase,
which in conjunction have been previously demonstrated in other
systems to cause mitotic catastrophe. We further find that the
cells undergoing HIV- directed PCD have profoundly excessive
levels of phosphorylated p34cdc2 kinase, reflecting hyperactivity
of the wee1+ kinase which is the cellular enzyme responsible for
cdc2 phosphorylation. Since overactivity of wee1 + kinase in
numerous systems has been shown to directly and dramatically
increase cell size, its overactivity in cells dying of HIV PCD
apparently explains the balloon cytopathicity seen in
HIV-infected cultures. This work is the first report defining a
basic cellular mechanism operative during virally-initiated
apoptosis. Because the mechanism of PCD utilized by HIV to kill T
cells apparently does not participate in normal T cell
development, HIV- mediated apoptosis appears to represent an
unusual killing program which potentially renders it more
susceptible to specific disruption by therapeutic agents.

Liegler TJ; Stites DP 
HIV-1 gp120 and anti-gp120 induce reversible unresponsiveness 
in peripheral CD4 T lymphocytes.
J Acquir Immune Defic Syndr
1994 Apr Issue/Part/Supplement: 4 Volume Issue: 7 Pagination:
340-8

Human immunodeficiency virus type 1 (HIV-1) gp-120 potentially
plays an important role in inducing functional suppression and
depletion of CD4 lymphocytes following infection with HIV. In order
to further understand the mechanisms involved in HIV-induced
immunosuppression, we have studied the effects of recombinant
HIV-1 gp120/SF2 and anti-gp120/SF2 antibodies on T cell receptor
(TCR)-mediated proliferation of peripheral blood mononuclear cells
(PBMCs) and isolated lymphocyte subsets from HIV-seronegative
donors. In a dose-dependent manner, gp120 significantly reduces
the proliferative responses of unfractionated PBMCs and highly
enriched CD4 T lymphocytes when they are polyclonally stimulated
through the TCR using WT31 (anti-alpha beta Ti chains) and anti-
Leu 4 (anti-CD3 epsilon) in the presence of autologous accessory
cells. The addition of divalent anti-gp120/SF2 to lymphocytes
previously incubated with gp120 further reduces the proliferation to
the levels seen after pretreating cells with divalent anti-CD4 (anti-
Leu 3a). CD8 T lymphocytes, on the other hand, show no change in
TCR-mediated proliferation following preincubation with either anti-
CD4 or gp120/anti-gp120. We find no evidence for significant cell
death by apoptosis using methods of DNA analysis or flow
cytometry and DNA-specific dyes to account for the loss of CD4
lymphocyte proliferation.  Interleukin-2 restores the proliferation
suppressed by gp120/anti-gp120 suggesting the induction of
reversible functional anergy.
 
Department of Laboratory Medicine, University of California, San
Francisco.



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