Newsday - February 9, 2001
Laurie Garrett

Chicago-A factor normally found in human placentas blocks the AIDS virus in laboratory studies and may naturally protect most fetuses from getting the virus from their mothers.

The chemical appears to be highly potent-in doses a thousand-fold smaller than those used in most of the current crop of anti-HIV medicines, said researcher Dr. Bruce Patterson of Children's Memorial Hospital in Chicago at the Eighth Annual Retrovirus Conference this week.

It has long been known that, even in the absence of drugs such as AZT, 66 percent of newborns escape infection from their HIV-positive mothers. The new research suggests that the naturally occurring protective ingredient is a small protein called leukemia inhibitory factor, or LIF. Its name is derived from a mild anti-cancer effect it exerts in mice.

Patterson, in collaboration with scientists at Northwestern University in Evanston, Ill., Rush Medical College here and the Karolinska Institute in Sweden, were trying to understand why, even in the absence of medicine, HIV-positive women usually give birth to HIV-negative babies.

Patterson's group analyzed 14 placentas from HIV-positive women who gave birth to uninfected babies, five placentas from women whose babies were HIV-positive and three uninfected mothers.

They discovered LIF in all of the placentas but levels of the factor were highest in the HIV-positive mothers who gave birth to uninfected babies. Patterson's team treated placental cultures in the laboratory with dozens of HIV strains. When Patterson added minute quantities of LIF to the cultures, HIV replication was blocked.

LIF also blocked HIV in cultures of children's thymuses, which in AIDS patients are typically rife with the virus.

LIF, a factor whose usual role in the body is unknown, Patterson said, attaches itself to special receptors found not only in placental cells but also on some types of immune system macrophages found in men and women. Nobody yet knows what role those cellular receptors usually play.

When HIV enters the cell, the bond formed between LIF and its receptor prompts the release of other, as yet unidentified chemicals, that prevent HIV from getting into the interior of the cell. Unable to travel inside the targeted cell, HIV cannot gain access to the human DNA and genetic materials it needs to copy itself. So, eventually, the virus dies, leaving no offspring.

Since LIF is a natural compound found in human beings, Patterson said, "a novel approach would be using the body's own defense mechanisms in the fight against HIV."

The small biotechnology company Virion in Michigan holds a patent on all HIV-related uses of LIF. (Patterson and his colleagues do not stand to profit, personally, from LIF drug development, he said.)

The company has already made LIF, at a cost of roughly $270 for 2,000 doses.

The researchers are moving toward clinical trials, which they hope will prove useful in a gel suspension, as a microbicide to protect women from sexual exposure to HIV.

Although LIF's effects must be proven in other laboratories, the existence of such a factor has been indicated for a long time. At this meeting, for example, the Centers for Disease Control and Prevention's Ann Duerr announced that a soluble suppressive factor, which she has not yet identified, protected HIV-negative wives in Thailand from their husbands' viruses. And for several years, Dr. Robert Gallo, director of the Institute of Human Virology in Baltimore, has insisted that a hormonal mixture found in pregnant mothers, human chorionic gonadotrophin or HCG, could suppress HIV. But HCG is a complex mixture, and Gallo has not isolated the specific factor.

Patterson said that LIF is Duerr's "soluble suppressive factor" and the agent responsible for Gallo's HCG effect on HIV.

In an interview, Gallo said he didn't think LIF and his HCG factor were structurally identical but said "I'd like to see the full sequences. Perhaps they share some sequences."

The LIF finding does seem to contradict one well-established hormonal finding announced last year by Dr. Preston Marx of the Aaron Diamond AIDS Research Center in Manhattan. In monkey studies, Marx showed that HIV most readily infects vaginal and cervical tissues when progesterone levels are highest. In contrast, Marx found, estrogen thickens the vaginal and cervical lining, forming a barrier against infection.

Patterson's LIF is stimulated by progesterone and can be found in largest quantity in women when their estrogen levels are lowest.

However, "LIF could be so potent that it's overcoming the negative impact of progesterone," Marx theorized in an interview.

There are many other novel approaches to HIV, some of which are well along in the pharmaceutical pipeline. Scientists at the conference learned that agents that block the ability of HIV to fuse with a cellular receptor, in a step vital to infection of the cell, are in the final stages of clinical testing. Several companies are also working on drugs that block other cellular receptors that form the doorway for HIV to enter the cell. And dozens of new forms of the already available anti-HIV therapies are in development.

But work on many promising compounds has stalled or stopped because of problems such as toxicity, Cornell University's Dr. Roy Gulick told the audience yesterday at the close of the conference.

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