IUBio

The HIV/CD4 Interface

James Kennedy jrken at ix.netcom.com
Fri Sep 8 19:33:24 EST 1995


The complementary interface between HIV and the CD4 molecule may be the
Rosetta Stone for the riddle of AIDS and may also shed some light on
the mechanism of peripheral tolerance.

The incontrovertible evidence supporting the existence of CD4 specific
CTLs in HIV infection (1,2)means that there is at least a component of
autoimmunity in AIDS and suggests that tolerance for the  CD4 molecule
is  mediated through a dynamic peripheral network which normally
protects CD4 lymphocytes from these CTLs.

Precursor HIV specific cells (3) and B cells with immunoglobulin VH3
gene products (4) are present in HIV negative individuals.   These
effector clones and CD4 lymphocytes are also the  natural ligands for
HIV and all of them disappear as  AIDS progresses.  Therefore, if CD4
specific CTLs are CD4 idiotopes, perhaps the HIV specific CTL and the B
cell VH3 clones are the anti-idiotopes of a tolerance network whose
equilibrium endpoint is shifted away from tolerance by the introduction
of HIV into the system. Carrying the network analogy further, CD4
specific CTLs may act as immune modulators by recognizing up regulated
CD4 lymphocytes and they are in turn brought under control by the
anti-idiotopes (5).

>CD4 molecule<   <CD4 spec CTL>    >HIV spec CTL & VH3 B cells<   <HIV>

There is evidence for self reactive immune components in many viral
infections.  In these three, the immune target is the viral receptor.
Ravindranath (6) found antibodies against both the CMV virus and its
receptor suggesting an idiotypic, anti-idiotypic network. In murine
coxsackie myocarditis Weller (7) discovered a clone of myocyte specific
CTLs and a monoclonal antibody which recognized the myocyte’s
coxsackievirus  receptor. The CTL clone was myocyte lytic and the
antibody was myocyte protective. Finally, in chronic hepatitis B
infections (8),  there are autoantibodies which attack the virus’
asialoglycoprotien  receptor. 


I realize that much of this evidence is circumstantial but there is a
strong enough case to warrant experimental evaluation. It would seem
that the ideal vehicle for the investigation of the complementary
peptides of the HIV/CD4 interface would be a mixed lymphocyte response
(MLR) using  cells from HIV negative subjects. Kion and Hoffman
essentially performed a MLR in vivo by injecting mice with allogenic
cells and subsequently demonstrating their production of gp120 specific
antibodies (9).  They concluded that the class II MHC molecule was the
HIV look alike.

The complementary peptides of the HIV/CD4 interface would have to be
evaluated for both cellular and humoral responses (including
complementary suppressor peptides (10)). In this instance, the
technology exists and the exact targets are known. The humoral
component could be evaluated with ELISA test using recombinant CD4 and
gp120, but  the cellular component may require gene transfection
techniques.



I would be happy to supply  references.  Comments and criticisms are
welcome.

J.R. Kennedy




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