CD4 Tolerance and HIV

James Kennedy jrken at
Sat Aug 19 14:08:23 EST 1995

While there are attractions to an AIDS etiology hypothesis where
immune exhaustion occurs because of the prolific, constantly
mutating, CD4 lytic, HIV virus and the presence of HIV specific
CTLs attacking infected CD4 cells, it does not seem sufficient to
bring down the system.

Some of the reservations are;  First, the immune system is hardly
worn out from chasing HIV's chameleonic antics. In fact, it does
not seem to even try . The diversity of the initial immune re-
sponse to HIV seems quizzically fixed [H. Kohler (1994)Im Today,
15,474-478]. While this does not seem particularly safe, an
immune attack on a critical HIV component, which can't afford to
mutate, means this response does not have to be fatal. At any
rate, the immune system doesn't wear itself out chasing it's

Second, it seems that AIDS would have to be an acute illness if 
HIV is even moderately CD4 lytic. The recent demonstration of
HIV's prolific nature would seem to require that direct CD4
destruction by HIV would have to be very limited in scope.

Third, consider the question of whether HIV specific CTLs are
pathologic because of the large number of CD4 cells which are HIV
infected?  This might be a valid consideration if it were not for
the fact that HIV specific cells disappear just like the CD4
cells and, in fact, the opportunistic infections that occur in
AIDS do not appear until after these CTLs are gone [A. Hoffenbach
(1990) J. of Im, 142,452-462].

Let us address another possibility. Consider the fact that there
are three immune components that are drastically reduced or
disappear entirely in AIDS -  CD4 cells, HIV specific CTLs, and B
cells whose membrane IgG display VH3 gene products [L.Berberian
(1993), Science 261,1588-1591]. Besides disappearing, what else
do these three have in common? They all share a complementary
interface with HIV and they all are present in HIV negative
individuals, [A.Hoffenbach- ibid] [L. Berberian - ibid ] . 
Could these 3 share that same interface with CD4 specific CTLs
which are present in HIV+ subjects [J.Zarling (1990)J. of Im
144,2992-2998] [M. Grant (1994) J. AIDS 7/6 571-579]? Do these
CD4 specific CTLs have T cell receptors with the immunologic
appearance of HIV's CD4 tropic area? And finally, are these CD4
specific CTLs the agents of CD4 depletion in AIDS?

                                 HIV specific CTL
     >CD4<  <CD4 specific CTL>  >----------------<   <HIV>
                                    VH3 B cells

What I am alluding to is naturally occurring peripheral tolerance
for the CD4 molecule which breaks down because of the presence of
HIV. In this scenario, idiotypic CD4 specific CTLs modulate
normal immune responses by attacking up regulated CD4 cells,
 [J. Kennedy (1993) Medical Hypothesis 41,445-449] . This CD4
specific response is controlled by anti-Id HIV specific CTLs and
VH3 B cells who have never met the HIV virus. HIV has the poten-
tial to shift the immunological balance of this immune modulation 
system and augment the CD4 destruction.

The above is possible and a timed sequential analysis of a mixed
lymphocyte response (cells from HIV negative donors) using recom-
binant GP-120 and CD4 could evaluate many of the components of
this hypothetical immune modulation system.


More information about the Immuno mailing list