A viral culprit suspected to be responsible for the disfiguring and potentially deadly tumors that affect many persons with AIDS is now in hand, scientists at the Howard Hughes Medical Institute (HHMI) at the University of California, San Francisco report. The researchers discovered a herpes virus that is implicated in the development of Kaposi's sarcoma (KS), an opportunistic disease that often afflicts individuals whose immune systems are weakened by AIDS. The discovery paves the way for the development of diagnostic tests to detect infection with the herpes virus.
The UCSF/HHMI scientists are the first to successfully reproduce the virus in the laboratory and to photograph it. The researchers' success now will permit the testing of anti-viral drugs in infected cells. In addition, scientists now can study the virus's life cycle and its strengths and weaknesses. Such knowledge could lead to more precisely targeted anti-viral therapies to combat KS. KS is a stigmatizing cancer in which blood vessel cells grow out of control, usually on the skin, where they form oval-shaped reddish-purple lesions.
While the incidence of the disease among AIDS patients has declined in recent years, it remains very common, and physicians continue to see patients with potentially life-threatening cases of KS in which the tumors attack the lungs or the gastrointestinal tract. Drug treatment for KS has been less successful than treatments for other frequently occurring complications of AIDS.The UCSF/HHMI research group that collared the virus is headed by Don Ganem, MD, professor of medicine and microbiology at UCSF and an HHMI investigator.
The UCSF/HHMI team grew the virus in cell cultures derived not from KS, but from a different, uncommon, AIDS-related lymphoma, a cancer of the immune system's B cells.An article presenting the research appears in the March issue of Nature Medicine, along with mug shots of the viral suspect, greatly magnified through an electron microscope.
The virus has been named KSHV, for Kaposi's sarcoma-associated herpes virus, or human herpes virus eight, as it is the eighth herpes virus known to play a role in human illness. Common maladies caused by other herpes viruses include genital herpes, cold sores, and chicken pox."The circumstantial evidence implicating this herpes virus in Kaposi's sarcoma is strong," Ganem says. "During the past year it has become clear that genetic fingerprints of KSHV appear in KS tumors far more often than in normal tissue, and that they also occur at a higher rate in individuals with AIDS compared to those without AIDS.
"Furthermore, AIDS patients exhibiting genetic evidence of KSHV infection are more likely to later develop KS than are those who appear uninfected by KSHV." Co-authors on the study include Rolf Renne, PhD, Weidong Zhong, PhD, and Dean Kedes, MD, PhD, all post-doctoral fellows; Brian Herndier, PhD, MD, associate professor of pathology and Michael McGrath, MD, PhD, associate professor of laboratory medicine, who together established the cell lines in which the virus was grown; and Nancy Abbey, a research associate.
The discovery of KSHV comes more than a decade after the identification of the AIDS virus itself, HIV. But the apprehension of KSHV occurs just one year after the first incriminating genetic fingerprints of the previously unknown virus were discovered within the DNA of tumor cells from patients with KS. That finding was made by Yuan Chang and Patrick S. Moore, a wife-and-husband team from Columbia University who were driven to look for a disease agent in KS by the growing epidemiological indications pointing to infection. Chang and Moore's discovery of viral DNA provided the first evidence of an infectious agent in KS and set off a scramble to track the virus down.Like other herpes viruses, KSHV consists of DNA encoding more than 70 genes, all wrapped in a protective coat. The virus delivers its DNA into host cells, and can order the cellular machinery of its host to churn out the building blocks of new, self-assembling virus particles.
The development of tests to detect immune antibodies to the virus in blood, an indicator of infection, will assist in epidemiological studies to better define the role of the virus in KS and to determine whether the virus is transmitted sexually or through other means, Ganem says. About 25 percent of homosexual men with AIDS are affected by Kaposi's sarcoma, while three percent or less of hemophiliacs with AIDS have the disease, Ganem says.
A small fraction of organ transplant recipients, who take drugs to suppress the immune system, contract KS. KS also occurs among many African populations, with or without HIV, and among elderly men from the Mediterranean region.Fifteen years ago, the appearance of KS, which had been nearly unknown in the US, was among the most striking findings observed by physicians in several fatally ill homosexual men on the West Coast. Its presence contributed to suspicions that a previously unidentified disease was afoot, one now known globally as AIDS.