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Cell stimulant touted as yet another cure—proceed with caution

Since the beginning of the AIDS pandemic, scientists have been testing a wide variety of compounds in the hope of eradicating or curing HIV infection. Sadly, so far none have worked. The latest compound to garner some potential role in helping the immune system is vitamin D–binding protein (DBP).

Over the past four decades DBP has undergone a few name changes as researchers have found new roles for it. When it was first discovered, DBP was called Gc because it was part of a larger group, or complex, of proteins. Later, researchers found it could help move vitamin D around the body, and it was called DBP. Most recently, scientists in Japan have been conducting experiments that suggest that DBP, when slightly modified by enzymes, can have stimulating effects on a group of immune cells called macrophages. Because DBP has stimulating effects on macrophages, it is sometimes called macrophage-activating factor.

More about these cells

Macrophages are an important part of the immune system and have many functions, including the following:

alerting the immune system about invading microbes
amplifying the immune system’s response to infection
attacking virus-infected cells and tumours

Made in…

Although the liver seems to make most of the body’s DBP, many other tissues also make this protein, and DBP has been found in the following:

blood
breast milk
spinal fluid
seminal fluid

DBP has also been found on the surface of many cells of the immune system as well as on sperm and muscle cells.

What does it do?

The full extent of DBP’s role in the body is not clear, but it appears to do more than help transport vitamin D.

Perhaps the most interesting aspect of DBP’s properties is its effect on the immune system, where it appears to help regulate the response to infection. Here is one theory of how DBP might work, based on the results of animal experiments:

When an infection occurs, the subsequent inflammation attracts B- and T-cells. These cells release enzymes that convert DBP into macrophage-activating factor (MAF). This compound helps macrophages fight infections. Then, almost magically, after the infection has been brought under control, MAF is supposed to help shut down an unneeded immune response. How this compound can change from an immune stimulant to an immune suppressant has not been clearly explained by proponents of MAF-based therapy.

Bear in mind that this is all theory and not well understood, perhaps even by its proponents. Based on results of experiments on cells and animals in the lab, Japanese researchers decided to study the potential role of MAF in HIV/AIDS. According to their findings, an enzyme that they have named nagalase (correct name: alpha-N-acetylgalactosaminidase) found in the blood of HIV positive people seems to inactivate MAF. Apparently nagalase is released by HIV-infected cells and seems to be found on HIV itself.

MAF

The research team has supposedly found a way of converting DBP to MAF in the lab. The team claims that in pilot studies of HIV negative people with cancer who had MAF injected into muscle once weekly for several months, the cancers were apparently cured.

Because macrophage dysfunction is an effect of HIV infection, the researchers expected that MAF would fix this problem and cure HIV infection. Their work, which we now assess, will be published in the January 2009 issue of the Journal of Medical Virology.

Study details

The team recruited 15 HIV positive people who were free of AIDS-related symptoms and who did not have anemia. They injected participants with 100 nanograms of MAF once weekly into muscle, for between six and 18 weeks.

Results

The team presented a few details on only five participants. In these five people, viral loads fell to low or so-called undetectable levels over the course of the first six weeks of the study. Bear in mind that the viral load assay used in the study had a lower-limit of quantification of 400 copies/mL. More sensitive assays with a lower-limit of quantification ranging between 75 and 40 copies/mL are routinely used in high-income countries such as Japan. That the MAF research team used an older and less-sensitive assay is unusual and suggests that its pilot study was done many years ago when high-sensitivity viral load assays were not yet available. As a result of using the 400-copy assay, it is possible that low-level viral replication that the assay could not detect was taking place in study participants.

In the remaining 10 participants, results of CD4+ assessments suggested that levels of these cells generally doubled after therapy with MAF and levels of CD8+ cells fell. The researchers claim that these high CD4+ counts were maintained for seven years after MAF therapy ended. There were no apparent side effects from exposure to MAF.

Caution and concerns

The immune system is extremely complex. Despite nearly 30 years of research since the appearance of AIDS, researchers do not fully understand precisely how HIV destroys the immune system. Because of its complexity, it is sometimes hard to explain the workings of the immune system. Historically, from time to time, seductively simplistic theories about how HIV causes disease or alternative causes of AIDS have been put forth. Yet, in the end, investigation of these simple theories has always proven them wrong. This will likely be the case with the results from the Japanese team.
It is against this background of simplistic theories that we encourage our readers to treat this latest idea of HIV-related dysfunction (and its so-called cure) with extreme caution. This warning is given added impetus because the same research team claims to have cured several different types of cancers in HIV negative people with the same therapy used for HIV. While AIDS and cancer are both the result of immune dysfunction, they have different causes, so a therapy for cancer is not likely to help people with HIV.
The MAF research team did not use the sophisticated techniques that have become the gold standard when trying to find HIV in eradication experiments. As a result, we cannot rely on its claims to have wiped out HIV. The team’s claims of curing HIV and cancer are highly premature and require confirmation by independent investigators.
Regrettably, the MAF team has been the only group of researchers to obtain the results that they did. They now have a duty to work with scientists in the field of HIV eradication who can confirm their theory, first in lab experiments with cells and perhaps later in monkeys infected with immune deficiency viruses such as SIV.
It is deeply disappointing that after nearly three decades the HIV pandemic continues to burn through communities and regions of the world. And, there is no effective vaccine or cure in sight. Given these circumstances, it is possible that an increase in claims of a cure may arise from time to time. In such cases, particularly when there are claims from researchers who are not embedded in the field of HIV/AIDS, we urge our readers to treat these claims with a healthy degree of skepticism.

—Sean R. Hosein

REFERENCES:

Schooley RT and Mellors JW. No cure yet for HIV-1, but therapeutic research presses on. Journal of Infectious Diseases. 2007 Mar 15;195(6):770-2.
Marsden MD, Zack JA. Eradication of HIV: current challenges and new directions. Journal of Antimicrobial Chemotherapy. 2008; in press.
Shen L, Siliciano RF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. Journal of Allergy and Clinical Immunology. 2008 Jul;122(1):22-8.
Palmer S, Maldarelli F, Wiegand A, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proceedings of the National Academy of Sciences USA. 2008 Mar 11;105(10):3879-84.
Gomme PT, Bertolini J. Therapeutic potential of vitamin D-binding protein. Trends in Biotechnology. 2004 Jul;22(7):340-5.
Yamamoto N, Suyama H, Nakazato H, et al. Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF. Cancer Immunology, Immunotherapy. 2008 Jul;57(7):1007-16.
Yamamoto N, Suyama H, Yamamoto N, et al. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). International Journal of Cancer. 2008 Jan 15;122(2):461-7.
Yamamoto N. Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the envelope glycoprotein gp160 of human immunodeficiency virus Type 1. AIDS Research and Human Retroviruses. 2006 Mar;22(3):262-71.
Yamamoto N, Kumashiro R. Conversion of vitamin D3 binding protein (group-specific component) to a macrophage activating factor by the stepwise action of beta-galactosidase of B cells and sialidase of T cells. Journal of Immunology. 1993 Sep 1;151(5):2794-802.
Yamamoto N, Ushijima N, Koga Y. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). Journal of Medical Virology. 2009 January;81(1):16-26.
Nagasawa H, Uto Y, Sasaki H, Okamura N, et al. Gc protein (vitamin D-binding protein): Gc genotyping and GcMAF precursor activity. Anticancer Research. 2005 Nov-Dec;25(6A):3689-95.

Created on: 12/15/2008

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