Researchers Suggest New Disease Model May Some Day Lead To Effective Drugs ForHIV-Associated Dementia

June 05, 1998

CHICAGO--Researchers have long believed that macrophages, the scavenger cells of the immune system, do not divide. They emerge from the bone marrow as monocytes, circulate in the bloodstream for three days, and then migrate into tissue, where they resume a variety of functional roles.

But in a plenary session of the Neuroscience of HIV Infection meeting here today, June 5, a UC San Francisco researcher proposes not only that these cells can divide under certain abnormal circumstances, producing identical daughter cells, but that when they do so they proliferate, affect neighboring cells and, as a result, in some cases cause disease.

While focusing on his latest findings regarding the proposed role of macrophage proliferation in AIDS dementia, Michael McGrath, MD, PhD, a UCSF associate professor of laboratory medicine, laid out a paradigm he calls "sequential pathogenesis," a process in which, he suggested, macrophages may be the key player in numerous cell-proliferation diseases, including AIDS-related lymphoma and dementia.

"Based on these studies, my colleagues and I have readjusted our thinking regarding some aspects of macrophage function," said McGrath. "We're suggesting that these replicating macrophages may be the cornerstone of some human diseases."

According to the theory of "sequential pathogenesis," HIV or, perhaps even some other genetic element, integrates itself into the genome of macrophages, next to one of several cancer-causing genes, causing these so-called oncogenes to be activated. The oncogenes then prompt macrophages to begin expressing growth factors that, in turn, trigger the proliferation of other macrophages and other cell types involved in a range of disease conditions.

McGrath and his colleagues, including Brian Herndier, UCSF associate professor of pathology, said that they have identified three different macrophage-associated oncogenes, c-fes and platelet derived growth factor A and B, as being involved in different forms of HIV-associated degenerative and proliferative diseases.

"Our theory is that, depending on where HIV integrates itself into the macrophage genome--thus determining which oncogene is turned on inappropriately--there will be an increased risk for development of cancer or dementia," said McGrath.

McGrath has previously reported elements of his paradigm in Cancer Research (1994), regarding HIV integration in HIV-associated lymphomas; in JAIDS (1995) regarding HIV-associated Kaposi's Sarcoma; and in Lancet (1997) regarding a blood test that identified elevated levels of activated macrophages in AIDS dementia.

Today, he presented data supporting a new model that he says suggests that AIDS dementia may be, in part, the result of a process involving HIV-infected macrophage division. HIV-infected macrophages have long been known to appear in large numbers in the brains of HIV-infected patients. Macrophages make many different factors harmful to the brain, and conventional strategies have sought to block the factors, unsuccessfully.

Now McGrath reports that, in AIDS dementia patients, HIV may integrate itself into the macrophage genome next to the platelet derived growth factor B oncogene. "We are showing proliferating macrophages in the brain expressing the PDGF-B product, and demonstrating that they are doing so in an area where there are increased numbers of astrocytes [cells that proliferate in response to the destruction of nearby neurons.]"

McGrath also reported that researchers have identified a class of DNA-interacting drugs related to polyamines that, he said, could be potential candidates for treatment of AIDS dementia.

"In a preliminary study, a single dose of the drug," he said, "killed dividing macrophages, and thus removed the production of substances that kill brain cells in vitro. By contrast, cytotoxan, a standard cancer chemotherapy agent, had little effect on these cells."

The technology regarding this newly described class of macrophages (therapeutic, prognostic and diagnostic) is being developed by SLIL Biomedical Corp., of San Mateo, CA.

University of California has received patents on the full technology platform, which includes potential diagnostic blood tests and drug therapies. McGrath and Herndier are chief scientific consultants to SLIL and principal founders of the company's Biomedical Analysis division.
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Notes to media:

To arrange an interview with Michael McGrath, MD, PhD, contact Jennifer O'Brien in the UCSF News Office, at 415/476-2557.

For information on SLIL Biomedical Corp., contact Carol Melis or Mike Jackman at 650/342-5686.

Two lay-oriented graphic images of "sequential pathogenesis," can be accessed at: http://www.pubaffr.ucsf.edu/news/photos/0605path.html

References:

Shiramizu BS, Herndier BG and McGrath MS. Identification of a common clonal HIV integration site in HIV virus-associated lymphomas. Cancer Research 54:2069-2072; 1994

McGrath MS, Shiramizu B, Herndier B. Identification of a clonal form of HIV in early Kaposi's sarcoma: evidence for a novel model of oncogenesis, "sequential neoplasia". JAIDS 8:379-385; 1995

Pulliam L, Gascon R, Stubblebine M, McGuire D, McGrath MS. Unique monocyte subset in patients with AIDS dementia. Lancet 349:692-695; 1997
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University of California - San Francisco

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