Hypothesis: Tolerance for the HIV receptor on the CD4 molecule is
accomplished by a peripheral network mechanism where it's immune
recognition by idiotypic immune cells is negated by it's
anti-idiotypic counterpart.
>CD4< <CD4 specific idiotopes> >anti-idiotopes<
The presence of HIV, whose CD4 tropic area has the appearance of the
CD4 specific idiotopes, has the potential to shift the equilibrium of
the above tolerance equation toward increased immune recognition of CD4
(1).
>CD4< <CD4 specific idiotopes> >anti-idiotopes< <HIV>
The above is supported by several findings. First, non-HIV infected
CD4 lymphocytes are recognized by CD4 specific CTLs. Zarling
originally demonstrated such CD4 specific CTLs in HIV+ subjects and
she also found that HIV infected chimpanzees did not have them (2).
More recently, Grant found CD4 specific CTLs attacking non-HIV infected
cells and showed that their presence was associated with CD4 lymphocyte
destruction (3). The fact that HIV infected chimps do not get AIDS and
do not have CD4 specific CTLs suggests that they may not MHC present
the appropriate CD4 molecule. That HIV infected humans without CD4
specific CTLs do not drop their CD4 counts is obviously significant.
CD4 specific CTLs
>CD4< <CD4 specific idiotopes> >anti-idiotopes< <HIV>
The anti-idiotypic component of the equation seems to best be
represented by certain B cells and CTLs. Berberian showed that
immunoglobulin VH3 gene products were natural ligands for HIV gp-120
and that such B cells disappeared with AIDS progression (4).Hoffenbach
demonstrated that HIV specific CTLs were CD4 protective and that they
disappeared before opportunistic infections appeared in AIDS (5). They
also showed that HIV specific precursor cells were present in non HIV
infected subjects . The above findings suggests that CD4 cells, VH3 B
cells and HIV specific CTLs share a common interface with HIV and also
with CD4 specific CTLs. This results in all of them being destroyed in
AIDS and HIV's minimal lytic potential suggests that CD4 specific CTLs
may be the culprit. The presence of HIV specific precursor cells in HIV
negative subjects adds credence to the possibility of a naturally
occurring immune modulation complex.
Pseudo HIV specific CTLs
CD4 specific CTLs HIV specific CTLs
>CD4< <idiotypic CD4 specific> >anti-idiotypic< <HIV>
VH3 B cells
HIV specific precursor cells
If the above immune effectors (CD4 specific CTLs, pseudo HIV specific
CTLs, and VH3 B cells) do indeed constitute an immune modulation
complex which non-specifically modulates immune responses, they should
vary quantitatively according to the state of the immune response.
Theoretically, individual detection of the above effectors may be
dependent on the chronology of the immune state. By the use of a mixed
lymphocyte response, with cells from HIV negative subjects, humoral
responses of this modulation complex could probably be detected with
recombinant CD4 and gp-120 molecules. The cellular components of the
MLR should be detectable using Grant's and Hoffenbach's techniques.
This etiology for the progression of HIV infection to AIDS
(modification of a naturally occurring immune modulation complex by
HIV) has not been evaluated and the evidence suggests it should be.
J.R. Kennedy
(1) Kennedy, J; (1993) Does HIV disrupt a naturally occurring immune
modulation system? Medical Hypothesis 41, 445-449
(2) Zarling , A; Ledbetter, J; Sias, J; Fultz, P; Eichberg J; et al.
HIV infected humans, but not chimpanzees, have circulating cytotoxic T
lymphocytes that lyse uninfected CD4+ cells. (1990)J. Immunol. 144,
2992-2998
(3) Grant M.; Smail F,; Rosenthal K. Cytotoxic T-lymphocytes that kill
autologous CD4+ lymphocytes are associated with CD4+ lymphocyte
depletion in HIV-1 infection (1994) J. Acquired Immune Defic. Syndr.
7/6 (571-579)
(4) Berberian, L; Goodglick, L; Dipps, T; Braun, J. Immunoglobulin VH3
Gene products: Natural ligands for HIV gp120. (1993) Science 261,
1558-1591
(5) Hoffenbach, A; Langlade-Demoyer, P; Dadaglio, G; et at. Unusually
high frequencies of HIV-specific cytotoxic T lymphocytes in humans.
(1990) J. of Immunol. 142, 452-462.
