HIV and T. pallidum

Colman Jones colman at ican.net
Sun Oct 5 12:32:10 EST 1997


The following message, posted on behalf of John B. Scythes, was also
sent to the Spirochete Research Discussion Group e-mail list. Any
responses can be directed to me c/o colman at ican.net

Sincerely,

Colman Jones



I am posting this message to the list in the hope of discussing some
long-standing concerns about syphilis and HIV that I cannot resolve,
concerns that have arisen again as a result of reading the R.T. Rolfs
paper in the July 31 NEJM. I cannot understand why the effect of HIV on
syphilis is so negligible, both in the clinical and serologic
presentation, and the treatment response. I would have expected a major
difference in the response between those with and without HIV. Others
have looked for this before, and the effect has always been negligible.

Syphilis should be opportunistic in the HIV population, and it seems not
to be. Bob Rolfs observed that early latents have a better serologic
response when HIV-infected (!). I can't see why he found just 541 cases
of all stages in so many years of recruitment. Where is the late
syphilis? We've seen so few late cases. Where has this disease gone?
Syphilis is a hundred times as infectious as HIV, and happenstance
treatment is rarely curative. We acknowledge treatment problems and
controversy in Lyme, but seemingly not in syphilis.

As a lay observer who has studied many infectious diseases and their
interaction with animal and human immune systems (and who has published
and given several medical lectures and rounds), I think we are twisting
the rules of infectious disease immunology to explain away a potentially
bigger problem with syphilis in this population. I mean to say that
everything I've been able to learn in some 15 years, there is no
immunologic memory in syphilis worth speaking of, and prior infection
offers no protection whatsoever to subsequent challenge. Only a small
proportion of humans reliably develop a G&C type IV DTH reaction upon
re-exposure. This lack of measurable immunity is echoed in fact sheets
published by both the U.S. National Institute of Allergy and Infectious
Diseases and the New York State Department of Health.

I guess I am worried that we don't fully understand syphilis - certainly
*I* don't. If I could be provocative, I think the Wassermann paradigm
for the diagnosis of the morbidity and mortality of syphilis is
insensitive. Today, in the 1990s, I might license an anti-lipoidal test
as a screen in low risk populations, and I think it has reasonable
sensitivity. But would we license it for use in a population at risk for
repeated exposure to the treponematoses? Every animal and human study
suggests that such a test is insensitive to detect re-infection, perhaps
in up to half of demonstrably re-infected experimental subjects.

Maybe the majority of syphilis has always been more silent than active.
August Von Wassermann egregiously appropriated Bordet's test to measure
the *sensitized* form of the disease, and the morbidity associated with
it. To pose a question, I would like to ask why we only study the
sensitized or active form of this disease. The immune response to
syphilis - a disease which is rarely resolved without *early* treatment
- wanes over time, and untreated infection leads to an irreversibly
non-responsive state, which leads me to suspect that some sort of
tolerogenic or immune-switching mechanism is operating in chronic
disease, as suggested by the late Tom Fitzgerald. Why else would E.W.
Thomas, a leading syphilologist who studied over two thousand patients,
conclude in 1949, "Within 2 years after infection, untreated syphilis
produces immune changes in the host which, with rare exceptions, are
permanent and make it impossible for tissues to react to subsequent
infection with development of early syphilitic lesions" (Syphilis: Its
Course and Management, New York: MacMillan, 1949, p.10)? Penicillin did
not change this observation (see Reynolds, F., Oxford Medicine (1948),
pp. 665-668).

This immune deviation suggested above is probably the underlying
mechanism in our "new" disease called AIDS. The idea I'm suggesting is
that chronic active sexually-related infectious diseases, and especially
syphilis, push the immune system against the normal effector cell
function. This switch is in the genes of the precursor and progenitor
subsets, hence an ineffectual and apoptotic CD4 line - just an idea.
Furthermore, the syndrome is likely centuries old, but we just now have
the tools to see what the consumptive cases had in common with the
herpes zoster and Kaposi's sarcoma cases - i.e., AIDS. So it may be that
we will never be able to treat AIDS effectively by attacking just HIV.
These people need a reconstitution of their lympho-poetic system
somehow.

Getting back to syphilis in people with HIV, Bob Rolf's group has done
an admirable job of looking at this problem if we assume that
ART/RPR/VDRL tests, and our clinical acumen, can measure the morbidity
of syphilis. However, I respectfully suggest that we have got it at
least partly wrong. Some cases of syphilis in the HIV population may be
super-infections. If we speculate that a large number of undetected
syphilis cases are hiding in the HIV-infected population, and the immune
response is weakened, with resulting undersensitive serology, then
direct detection of T. pallidum is our only choice. Tests in bodily
fluids have always been insensitive, except in early syphilis, and I
suggest the use of PCR and DFA in the lymph nodes with the typical AIDS
architecture, regardless of syphilis serology or history (along the
ideas of Zoechling, N. et al., British J. of Dermatology, May 1997, and
Sheila Lukehart's group, J. of Clinical Microbiology, June 1997).

Colman Jones and I submitted an abstract to the VenSouth '97 IUVDT
HIV/STD World Congress that took place in Melbourne, Australia, in June
of this year. The paper was accepted for a co-plenary presentation in
the oral sessions. My presence at the meeting was privately solicited by
the scientific chair, Dr. Peter Meese, but I ended up not attending this
time. I include this abstract as a closing summary to this post, because
I think we need to fundamentally reassess the spectrum of immune
responses to, and interaction of, these two infections. I cannot
resolve, from an immunologic point of view, the observations of the R.T.
Rolfs study. If any list members are attending the ISSTDR in Seville
later this month, I am on a paper and would very much enjoy discussing
these concerns at the conference.

A basic research proposal adding to the above ideas can be found at
http://www.geocities.com/~colman/research.html , a 1995 discussion on
sci.med.aids at
http://www.radio.cbc.ca/programs/ideas/Aids/aidsnews.html , and other
published abstracts at
http://www.radio.cbc.ca/programs/ideas/Aids/scythes.html

Kindest regards,

John B. Scythes


SPECTRUM OF CELLULAR IMMUNE RESPONSES
TO THE HUMAN IMMUNODEFICIENCY VIRUSES
AND THE HUMAN TREPONEMATOSES

John B. Scythes, Colman M. Jones, Community Initiative for AIDS
Research, 32 Beaty Avenue, Toronto, Ontario, Canada M6K 3B4 (e-mail
colman at ican.net)

Most successful human pathogens induce a spectrum of immune responses in
their hosts, ranging from the protective DTH Th1 (cellular) type, to the
predominantly humoural and sometimes ineffective Th2 type. This latter
response, coupled with the other down-regulation of Th1 DTH, is
associated with chronic active infections, especially viruses and other
intracellular organisms, including HIV and T. pallidum.

Strong, seemingly protective, HIV-specific Th1 type responses - and even
virus isolation - have been documented in many individuals who do not
subsequently seroconvert. The global phylogenetics of HIV-1 suggest that
the virus has been in human populations for centuries, perhaps
millennia. It is therefore possible that most people exposed to HIV
develop effective Th1 type responses and will not develop chronic active
disease in the absence of co-factors intrinsic to their AIDS risk group.

Venereal treponematoses may be one of these co-factors. Infection with
T. pallidum results in somewhat effective Th1 type responses in early
syphilis, while immune deviation away from protective cellular immunity
is the norm in late disease. Syphilis remains conspicuously absent as an
opportunistic complication in AIDS, despite millions of untreated or
inadequately treated cases worldwide prior to the current epidemic.
Furthermore, many persons with HIV-associated B-cell polyclonal
activation have been found to selectively switch off some or all clones
making antibodies to T. pallidum, while antibodies to other infections
remain, raising questions over the reliability of current syphilis
diagnosis. Supplemental diagnostic tools, such as PCR and DFA on tissue,
may be needed to reliably exclude ongoing syphilis in persons with
sexually-acquired HIV disease. The immunoregulation of repeated
treponemal infections should be reassessed in an animal model.

(end of abstract)

P.S. HIV has consumed at least $40 billion with no vaccine in sight (and
a thousand isolates that cause disease!!??). I feel T. pallidum
deserves, say $100 million, to try to answer all those unsolved
questions that penicillin *seemed* to take care of. It is my respectful
suggestion that a successful syphilis vaccine would do more to control
AIDS and susceptibility to HIV than any HIV-based vaccine, and cost us
all a lot less than the current HIV=AIDS approach.



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