Berlin Conference: HIV Miscellaneous, Part I

The IX International Conference on AIDS, Berlin, June 6-11,
1993, included thousands of presentations. This mass of
information is difficult to organize, report, or otherwise
know what to do with. But there are some overall organizing
principles:

* Much, if not most, of the information is unlikely to be
useful to anyone, often because it consists of reports of
whatever data some doctors or scientists happened to have on
hand, unrelated to any particular rationale or purpose.

* Most of the information which is potentially useful fits
into larger topics (for example, particular treatments or
classes of treatments which are being actively developed,
such as protease inhibitors, or therapeutic vaccines, or
other treatments already in major human trials). These larger
topics are not covered below, since each one needs a
separate, longer article to describe the Berlin results
within the larger context of other information which is
available. Just saying what happened in Berlin would either
be misleading, or would require the reader to already
understand the previous history of the treatment, and we do
not assume that when writing AIDS TREATMENT NEWS.

Still, there were some miscellaneous presentations in Berlin
which we found interesting enough to report, but which may
not fit into larger articles which we are likely to publish.
Some of these reports are treatment ideas, and others are
theories about the pathogenesis of HIV disease (how the
disease develops).

The selection below was guided by photographs we took of some
of the posters in Berlin. In most cases, we ended up relying
on the published abstract; the pictures of the actual poster
did not change what we wrote. But in some cases the
photographs were important -- especially on allergy and HIV,
and also on the immunosuppressive peptide, both in the HIV
pathogenesis section, below.

To keep this article focused, we restricted it to HIV disease
(as opposed to opportunistic infections, etc., which might
become a separate article), and to posters instead of oral
presentations (which usually require a longer article).

The selection below is largely arbitrary and not at all
complete. When we finish analyzing our photographs, and the
published abstracts, we may publish reviews of other
presentations.

HIV Pathogenesis

Allergy and HIV: A report from Greece found that patients
with HIV who had allergies had a faster drop in T-helper
count than those without allergies -- and that the two may
have benefited differently from different treatments. Allergy
was detected by a questionnaire, and by skin and blood tests.
Both asymptomatic patients and those with AIDS had a more
rapid decline in their counts if they had allergies than if
they did not, and the difference was statistically
significant. The researchers also found in the allergic
patients, AZT alone did not increase T-helper counts of
patients with AIDS -- as it did in non-allergic patients. But
alpha interferon (Intron) "helps the (T-helper count) in
allergic patients to come even to a higher level than that of
the non-allergic."

These conclusions were based on experience with a total of 80
HIV-positive patients. T. Dikeakou and others, Contribution
of Allergy to the Establishment and Evolution of HIV
Infection, abstract #0422.

Comment: One way to follow up on this potentially important
report would be for physicians to check their records
(perhaps with the help of research specialists provided by
community-based research organizations, or by pharmaceutical
companies interested in improving the usefulness of their
products) to see if their experience has been consistent with
it.

Sjogren Syndrome, Parotiditis. These conditions which are
believed to be autoimmune seemed to be associated with slower
progression of HIV disease, in a prospective cohort of 35
patients at an autoimmunity clinic in Brazil. The authors
remarked that Sjogren syndrome is unusual in young men. M.
Neto and others, Parotiditis and Sjogren Syndrome are
Associated with Better Outcome and Longer Survival, abstract
#0421.

Apoptosis. A number of posters concerned apoptosis, or
programmed cell death, indicating an increasing interest in
this possible mechanism of depletion of immune-system cells
in AIDS. Apoptosis, which can be recognized in the laboratory
and distinguished from other ways cells can be killed,
results from a genetic program built into the cell.

It is believed that apoptosis is necessary early in human
development, as part of the process by which the immune
system learns to distinguish "self" from "non-self" -- so
that it will attack foreign bacteria, viruses, etc. but not
the body's own tissues. According to this widely held theory,
during the development of the fetus, the body creates a great
many different kinds of T-cells by random combinations. Many
of these cells would be activated by the body's own proteins;
others would not. At one point in development, something
turns on the genetic program for apoptosis; then those cells
which are activated die, while those which are not survive.
In adult life, after a person's immune system has developed,
apoptosis should not occur; the genetic machinery for it is
still there, but it should be turned off. Abnormal apoptosis
is believed to occur in persons which HIV.

Some of the posters exploring apoptosis in HIV disease are:

* F. Pandolfi and others, Increased Rate of Death by
Apoptosis In Vitro in Cells Isolated from Patients with HIV-1
Disease, abstract #0215. This poster noted that both IL-2,
and fibroblast-conditioned medium, reduced cell death in
laboratory tests.

* N. Kobayashi and Y. Nakanishi, Induction of Apoptotic Gene
by HIV Infection, abstract #0267.

* A.G. Laurent-Crawford and others, Induction of Apoptosis in
CD4 Lymphocytes by HIV Envelope Glycoproteins, abstract
#0278.

* M.A. Rey and others, HIV-2 EHO Is a Highly Cytopathic and
Divergent Virus That Induces Single Cell Killing by
Apoptosis, abstract #0279.

* G. Lombardi and others, HIV-1 Gp120-Dependent Induction of
Apoptosis in Antigen-Specific Human T-Cell Clones, abstract
#0282.

* N. Oyaizu and others, Apoptosis Inducing Mechanisms
Resulting in CD4+ T Cells Depletion, abstract #0314.

Immunosuppressive peptide. One theory of how HIV causes
damage is that a small part of one of the HIV proteins mimics
a crucial part of a protein used in the immune system. This
could cause dysfunction either by generating too much of the
substance, or by causing the production of antibodies against
it.

One research team suggested that a particular sequence of
eight amino acids (positions 583 to 590 in gp41) might be
critical. This sequence is highly conserved not only in HIV,
but also in other retroviruses -- including cancer-causing
viruses which are also known to cause immune suppression.
("Highly conserved" means that this sequence does not change
as the virus mutates, suggesting that it is essential in some
way for retroviruses.) The researchers suggest that whether
or not a retrovirus causes disease in a particular species
may depend on whether or not in can reproduce well enough in
that species to create enough of the immunosuppressive
sequence to cause serious problems. J. Denner and others, The
Immunosuppressive Peptide of HIV-1: Functional Domains and
Binding to Lymphocyte Surface Proteins, abstract #270.

Potential Treatments

The following posters report early laboratory work on
potential treatments. This section omits treatments which are
approved or being intensively developed. Instead, it focuses
on possibilities which are getting little attention and could
slip through the cracks.

Nanoparticles. Nanoparticles are small particles designed to
be taken up by monocytes and macrophages, which normally
ingest bacteria and other potentially harmful substances. The
idea is to deliver drugs efficiently to these particular
cells. Nanoparticles are ingested efficiently by macrophages
from persons with HIV, regardless of the stage of the
disease.

In laboratory tests, nanoparticles with a payload of AZT or
ddC showed no advantage over the free drug. They might be
more useful for drugs which are not water soluble or
otherwise are difficult to deliver. V. Sch
fer and others,
Inhibition of HIV Infection In Vitro by Antiviral Drug
Targeting Using Nanoparticles, abstract #565.

Ethyloxime 25. This is a reverse-transcriptase inhibitor
being developed by Hoechst AG and Bayer AG in Germany. A.
Paessens and others, Dibenzoazepindione Oximes: A New Class
of Allosteric Inhibitors of HIV-1 Reverse Transcriptase; Part
2: Biological Characterization, abstract #0617.

Active ether lipids. Kucera L. and others, Novel Membrane
Active Ether Lipids that Inhibit HIV-1 Induced gp 160/120
Functional Expression and Pathogenesis, abstract #0578. This
substance is believed to block interactions between infected
and uninfected cells.

Melittin. M. Wachinger and others, Amphipathic Peptide
Melittin: Inhibitory Effects on HIV-LRT Activity, HIV-RNA
Levels, and HIV Protein Expression, abstract # 0072. Melittin
has been found to reduce activity of the HIV LTR (long
terminal repeat of HIV, which makes the virus more active).
[Note: Do not confuse "melittin" with "melanin."]

Glycyrrhizin. Glycyrrhizin is a chemical found in licorice;
AIDS TREATMENT NEWS noted its potential anti-HIV use in
November 1986, and in May and in November 1990. Most of the
interest in glycyrrhizin for HIV and other viral infections
has been in Japan. A poster in Berlin presented results of a
Japanese study with 16 patients, ten of whom started the
treatment between 1986 and 1987. "In the treated group,
neither progression of immunologic abnormalities nor
development to AIDS has been seen." K. Akatani and others,
Prophylactic Effect of Long-Term Oral Administration of
Glycyrrhizin on AIDS Development of Asymptomatic Patients,
abstract #0596.

Note: In the U.S., a few people with HIV have been using the
same tablets (Glycyron brand) as tested in this study, but as
far as we know this potential treatment has never caught on
widely. There may never be enough momentum to do a definitive
test of glycyrrhizin as an anti-HIV treatment, at least not
in the way that major trials have been done in the past. We
hope that newer antiviral tests will make it possible to get
clear results quickly in relatively few patients; then a
community-based research organization could organize and
finance small trials, and we might have better information
about whether, or when, the treatment is helpful. What is
holding this back is that (1) the most desirable tests, such
as QC PCR or the branched DNA assay, are not widely available
at present, and (2) these tests have not yet been validated
with clinical results (to show that a drug which improves the
test result also improves the long-term prognosis of
patients). Hopefully the validation can be done on blood
samples frozen years ago in clinical trials, so that it is
not necessary to wait for years before a test is considered
adequately validated. And hopefully, too, the medical
community and the public will not allow the understandable
desire for validation to get out of hand. If a drug reduces
viral activity in patients and is reasonably safe, it should
be allowed to be used in medical practice until something
better is available.