Ritonavir works by reducing DHEA

James Howard phis at sprynet.com
Tue Sep 10 04:00:24 EST 1996

I contend that protease inhibitors produce their effects by reducing
production of DHEA.  

I.  My work suggests that low DHEA results in vulnerability to HIV
infection.  If DHEA is sufficiently high, the infection is removed
prior to antibody formation.  That is, infected T cells are
identified, attacked, and destroyed immediately.  This occurs before
the antibody sequence can occur.  Their is evidence that DHEA
increases significantly during the early phases of HIV infection
(Journal of Acquired Immune Deficiency Syndromes 1992; 5: 841).  As I
just suggested, I think this is the normal response to infection; in
people with high DHEA, this finishes the job.  In the citation just
given, it is also found that in all individuals in the study, the
backup supply of DHEA, called DHEA sulfate (DHEAS), is lower than
controls.  This indicates that the initial response of DHEA to the
infection is never sufficiently high for a complete removal of the
virus, and these individuals cannot replenish their supply of DHEA to
ever reach the proper level.  Another paper, in 1993, found that DHEAS
levels were significantly low.  "When analyzed by clinical subgroups,
significant differences were also found with a decrease in DHEA-S
levels seen in persons with more advanced illness." Am. J. Med. Sci.
1993: 305: 79.

If the levels of DHEA cannot ever reach the concentration sufficient
to complete the removal of HIV-infected cells, the DHEA response
becomes chronic.  That is, the DHEA response persists, because it is
chronically stimulated by infected cells.  Is this hypothesis correct?
Well, it would predict that some individuals exist whose DHEA level is
high enough to eradicate the HIV.  Individuals have been identified
who are proven to have been exposed to the virus, but did not develop
even the antibody response.  Below this, one should see differences in
DHEA levels according to response to the virus.  That is, individuals
who respond dramatically to the viurs will use their DHEA more rapidly
for their response than those who respond less actively with their
DHEA.  How can the response be identifed?  As I suggested, a
sufficient DHEA response will remove infected CD4s.  If, however, the
response becomes chronic, the numbers of CD4s should lessen at the
very same time that DHEA is reduced.  You see, the longer this chronic
killing of CD4s occurs, the more DHEA is needed.  DHEA is low in HIV+
and lower in AIDS (Journal of the American Medical Association 1989;
261: 1149).  Is this due to DHEA, I think so.  When DHEA is given to a
group that has never been exposed, the CD4s decline (American Journal
of Obstetrics and Gynecology 1993; 169: 1536).  Additionally, it is
known that exercise increases DHEA.  When forty to 60-year old men
perform anaerobic exercise, their CD4 decrease (Int. J. Sports Me.
1995; 16: 2).  DHEA increases cause CD4s to decrease.  The CD4
reduction should occur in other viral infections for the same reason.
For example, one study found this pattern in HIV infection and also in
infectious mononucleosis but not in HIV non-converters or
HIV-seronegative patients (AIDS 1995; 9: 561).

If I am correct, DHEA should be lower in those that constantly reduce
their CD4s, than in those that reduce their CD4 less rapidly.  That
is, DHEA should be used most in those that kill the most CD4s.  This
is directly supported in the following quotation.

JW Mulder, Frissen PH, Krijnen P, Endert E, de Wolf F, Goudsmit J,
Masterson JG, Lange JM, "Dehydroepiandrosterone as Predictor for
Progression to AIDS in Asymptomatic Human Immunodeficiency
Virus-infected Men.," J Infect Dis 165: 3, 413-8, Mar, 1992.

"The steroid hormone dehydroepiandrosterone (DHEA) has been reported
to protect against certain viral infections in animal models and to be
a modest inhibitor of human immunodeficiency virus type 1 (HIV-1)
infection in vitro. Serum DHEA levels were determined in 41
asymptomatic HIV-1-seropositive subjects, who progressed to AIDS
within 5 years after entering a cohort study, in 41 HIV-1-seropositive
controls, who remained asymptomatic, and in 41 HIV-1-seronegative
controls. At entry, DHEA levels were higher in the seronegative group
(median, 13.3 nmol/l) than in either the seropositive nonprogressors
(median, 9.2 nmol/l; P =.01) or the progressors (median, 7.2 nmol/l; P
less than .001). DHEA levels in the progressors approximately 5 months
before the diagnosis of AIDS were lower than the levels in the
nonprogressors after the same follow-up (median, 5.6 vs. 8.8 nmol/l; P
= .007). DHEA levels less than 7 nmol/l and CD4+ cell counts less than
0.5 x 10(9)/l both proved to be independent predictors for disease
progression in HIV-1-infected men."

My work suggests that DHEA is directly involved in replication and
transcription of DNA.  Anything that interferes with the availability
of DHEA will reduce transcription of DNA.  One of HIV characteristics,
since it is a retro virus, is that its genes are transcribed when the
DNA of the host cell is transcribed.  Reducing DHEA in a person should
reduce the viral transcripts.  Ritonavir dramatically reduces the
plasma HIV-1 RNA and increases CD4 counts in the person, i.e., in vivo
(New England Journal of Medicine 1995; 333: 1528).

I suggest ritonavir causes these effects by inhibiting production of
DHEA.  Inhibiting DHEA will stop the response of DHEA to infected
CD4s.  This will stop the removal of CD4s.  If DHEA is reduced enough,
transcription of HIV DNA within infected CD4s will also slow, or stop.
Therefore, the plasma levels of HIV RNA will decrease dramatically.

While Medline will not pull up "ritonavir" and any word associated
with the liver, or liver enzymes, various AIDS groups have reported
that ritonavir inhibits a liver enzyme called P 450.  Another protease
inhibitor, L-754,394, designated as a potent anti-HIV agent, can be
found by Medline to cause inhibition of this enzyme group.  There are
no studies of these protease inhibitors and the adrenal glands, the
source of DHEA.  It takes a lot of ritonavir, in the human, not in a
tissue culture dish, to produce the effects that I think are due to
reductions in DHEA.  I suspect that it takes this much drug to
effectively close down the P450 group of enzymes in the adrenal gland.
It has been suggested that loss of P450c17 in the adrenal gland with
age is the cause of the normal loss of DHEA with age.  "These results
suggested that the expression of P450c17 mRNA decreased in aged bovine
adrenal, which may cause the age-associated decline in biosynthesis of
adrenal androgen." Gerontology 1991; 37: 262.

There are other indications that the protease inhibitors are producing
their effects by closing down production of DHEA within the body, but,
for sake of brevity, I will close with this:  Ritonavir may be
producing its effects by reducing DHEA.

James Howard

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