First, let me calm the minds of those who might read the title and
think that this another "HIV ain't the eteliological agent" spinnoff.
HIV does cause AIDS but not throught the demise of the CD4 compartment.
The slow and continuous drop in CD4 cells happens because the target
molecule for viral entry is CD4.
However, this is incidental to the real cause of the disease: an
eventual failure of the CD8 compartment to kill the virally
infected cells. CD8 cells are ubiquitously CD4 positive at some
point in the developmental process. These cells are mainly
responsible for clearing viral infections.
Thus, CD8 cells are the "real" victims. However, nobody
is looking at these cells for two reasons: 1.)There is no detectable
proviral integration in the peripheral CD8 compartment. 2.)There is
no noticible drop in the CD8 count.
CD8 counts _should_ be higher during a viral infection. Thus,
the lack of an overall decline in CD8 cells is far from surprising.
CD4 cells remain targets throughout their lifetime, because
they (obviously) don't lose their CD4 expression. So, the impact
on the CD4 population should be greater than for CD8 single positives
which eventually (obviously) lose their CD4 positivity. However,
the clinical entity develops when the CD8's can't clear the
infection anymore and thus there is a drastic loss of CD4 cells.
That's why bacterial infections (read loss of CD4 response) usually
come first, followed by viral infections and cancers (read CD8 loss)
in the pathological progression of the clinical entity known
as AIDS.
Why then, is there no (detectable) residual integration of HIV
in the CD8 compartment? A bit surprising, since these cells
are derived from CD4+CD8+ "targets"...indeed the most vulnerable
targets in the thymus (Stanley et al, 1993)...For the answer, we
need to look at what the Ras folks have been doing. HIV
is known to cause apoptosis in the cells that it infects. And
which cells are most sensitive to apoptosis? Immature lymphocytes
(read Cd4+cd8+ cells)! So, there you have it. The RAS folks
are probably on the right track, but they're mostly looking at
CD4 single positive cells (the ones they mistakingly think are
the main targets for AIDS pathogenisis) and not the CD8 precursers
which are far more important in controling a viral infection
then CD4 cells.
This is probably also why HTLV-1 doesn't cause AIDS
even though it is CD4 tropic. HTLV contains TAX, which transforms
cells (prevents apoptosis). So, we can detect small amounts
of HTLV-1 in the CD8 compartment in healthy carriers.
This is also why adult infections have different pathological
consequences than infections that occurr in childhood, due to
the relative size of the REAL TARGET COMPARTMENT, the CD4 CD8 double
positives...
A penny--no make that a yen, for your thoughts. ;)
Christopher J. Savoie
Department of Genetics
Medical Institute of Bioregulation
Kyushu University
Fukuoka, Japan
savoie at bioreg.kyushu-u.ac.jp
