AIDSWEEKLY Plus, Monday, 7 July 1997
Daniel J. DeNoon, Senior Editor

A peptide isolated from human chorionic gonadotropin (hCG) reduced HIV viral load by as much as 2 log[10] in a preliminary clinical study.

The peptide, dubbed HIV associated factor C or HAF-C, is the most potent of several HIV inhibitory peptides isolated from hCG by Robert C. Gallo and co-workers at Gallo's Institute of Human Virology at the University of Maryland, Baltimore.

"There was a 0.7 to 2 log reduction in viral load; it varies widely among people," Gallo said. "The majority of treated people have high CD4 counts."

Gallo announced the findings in his opening address to "New Opportunities for HIV Therapy - From Discovery to Clinical Proof-of-Concept," the 2nd Joint Conference of the National Institute of Allergy and Infectious Diseases (NIAID) Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) and the National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV), held June 22- 26, 1997, in Vienna, Virginia.

"We can't get to the identity of the [HAF] peptides yet," Gallo said, noting that intensive studies are underway to fully characterize the factors.

Gallo said that rhesus macaques were treated with HAF-C after experimental infection with pathogenic SIV. Treatment resulted in decreased viral load and increased numbers of CD4(+) T cells.

HAF was also effective against Kaposi's sarcoma (KS).

"AIDS KS lesions undergo apoptosis in the presence of HAF," Gallo said.

Researchers at Gallo's lab were the first to show that hCG is active against KS. The finding was accidental, or, as Gallo put it, "a mistake with unconscious intention." Male and female nude mice were housed together shortly before transplantation with KS-derived KSY-1 cells. The cells induce metastatic cancer in the immunodeficient nude mice, but some mice surprisingly did not develop tumors. It turned out that they were pregnant.

Later studies showed that sera obtained from murine and human females in the early stages of pregnancy could inhibit KS; the anti-KS factor turned out to be the beta chain of the pregnancy hormone hCG.

University of Southern California researcher Parkash S. Gill and colleagues, working in collaboration with Gallo, reported at the 1996 Retrovirus conference that intralesional injections of hCG dramatically reduced KS lesions in AIDS patients. Later studies, reported in the October 24, 1996, issue of the New England Journal of Medicine, showed that KS lesions vanished in 10 of 12 subjects who received the highest doses of the most effective hCG preparation (see AIDS Weekly Plus, February 19, May 26, and November 11, 1996).

Gallo said that hCG obtained very early in pregnancy is most effective. Since commercial hCG preparations are pooled, efficacy varies from manufacturer to manufacturer and even from lot to lot.

"We stumbled on something very important," Gallo said. "hCG will prove to have many more benefits than previously thought. (beta)hCG doesn't appear early in pregnancy for nothing."

The direct anti-HIV effects of maternal hormones were first reported by Abner Notkins of the U.S. National Institute of Dental Research (NIDR). Notkins was studying transgenic mice engineered to contain an incomplete set of HIV genes in the DNA of every cell in their bodies. The virus could not reproduce, but could trick certain mouse cells into making many of the viral proteins. Baby mice that inherit HIV DNA from each transgenic parent eventually accumulate enough viral protein that they develop skin lesions, wasting syndrome, and die within three to six weeks.

Notkins and colleagues first recognized that maternal hormones might have a protective effect against HIV when they observed that newborn transgenic mice appear normal in size and weight, but soon show marked growth retardation. By eight days of age, they weighed 60 percent less that their normal littermates. It appeared to the investigators that the baby mice were protected by maternal hormones during pregnancy, and became susceptible to the effects of HIV once the level of hormones dropped dramatically at birth.

Further experiments showed that when the mice were treated with hCG, the majority of the animals showed normal weight gain as long as they were receiving the hormone. Furthermore, their cells produced considerably less viral protein than animals not receiving hormone treatment, and skin lesions were reduced dramatically. The study appeared in the April 2, 1997, issue of The Journal of Clinical Investigation (see AIDS Weekly Plus, May 5, 1997).

Gallo suggested that HAF or similar factors could explain why KS occurs 15 times more frequently in men than in women regardless of clinical setting.

The AIDS researcher also used the opportunity of his address to question whether HHV-8 -- now also known as KS herpesvirus or KSHV -- can directly cause KS.

"HHV-8 epidemiology does not describe the predisposition of men to KS," Gallo said.

According to Gallo, HHV-8 prevalence in Gambia is approximately 85 percent and yet AIDS KS is rare -- possibly because the prevalent AIDS virus is HIV-2 and not HIV-1.

He predicted that HHV-8 would be shown not to be a transforming virus, and that HHV-8 would prove to have an indirect or even "passenger" role in AIDS KS.

It has long been Gallo's contention that HIV-1, particularly the HIV-1 Tat protein, is integral to AIDS- associated KS. "We think the role of HIV [in KS] is not passive. It is influenced by Tat cytokines," Gallo said.

He noted that while vascular endothelial cells have been implicated as the spindle-shaped cells characteristic of KS lesions, other types of cells can take on the spindle shape.

"HIV infection leads to an increase in inflammatory cytokines, including interferon gamma," Gallo said. "Interferon gamma changes the shape of endothelial cells."

Gallo suggested that KS may not always be a malignancy, but noted that this is a controversial question.

"In my mind there are two ways of looking at KS," he said. "Either it is a malignancy from day one, or it always begins as hyperplasia and then sometimes progresses to neoplasia."

In Gallo's typical fast-paced, wide-ranging talk, he also touched on the lightning pace of research stimulated by his laboratory's finding that the chemokines RANTES, MIP-1(alpha), and MIP-1(beta) exert anti-HIV effects. The finding quickly led to the discovery of cellular co-receptors (CC) for HIV.

Gallo observed that the importance of the CC chemokines is underscored by their elevated presence in HIV infected long- term nonprogressors and in people who remain uninfected despite repeated exposure to the virus.

"We believe it will play a role in AIDS vaccines: that's why we got into this," Gallo said.

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