AIDS Treatment News #181 - Aug 20 1993
John S. James

* 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.

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