July 5, 2000 A virus that causes a common form of AIDS-related cancer sabotages the body's immune system in a novel and previously unsuspected way, UCSF scientists have discovered.
When the virus associated with Kaposi's sarcoma (KS) invades a cell, two of the KS virus genes direct the cell to remove sentries posted on the cell surface and ship them to the interior for destruction, the researchers report.
The sentries -- proteins of the major histocompatibility complex, or MHC-1 -- constitute one of the cell's major lines of defense, and would otherwise tag the invaders for quick attack by the host immune system.
Other viruses sometimes disarm this line of defense too, but typically by blocking deployment of the sentries rather than getting the cell to recall them and target them for internal destruction. The approach evolved by the Kaposi's-associated herpesvirus (KSHV) is a novel strategy in the arms race between viruses and the immune system, says Donald Ganem, MD, an investigator of the Howard Hughes Medical Institute and professor of microbiology and immunology at UCSF. Ganem is senior author on a study describing the new research.
In the virus-immune system arms race, each new deployment by one side is met with a riposte from the other, Ganem says. "And there's every reason to believe this race isn't over. With every new strategy for host defense comes a selective pressure for the virus to find a way to circumvent that defense."
The research describing the KS virus genes and their function in immune sabotage is published in the current issue of the Proceedings of the National Academy of Sciences. First author is Laurent Coscoy, PhD, an HHMI postdoctoral researcher in Ganem's lab.
One of the intriguing findings in the new research is the discovery that the two proteins responsible for sequestering the MHC sentries and tagging them for destruction -- the process known as endocytosis -- do not act at the site where this action occurs, not even in the same subcellular compartment, the scientists report.
"We were surprised to discover that whereas the MHC-1 is engulfed by structures called endosomes near the surface of the cell, the viral proteins are localized in the interior of the cell, in the endoplasmic reticulum," said Coscoy.
Coscoy suggests two models for how this could occur: Either a very small population of the viral proteins -- too small to be detected experimentally -- travels to the cell membrane to cause MHC-1 to become vulnerable to the cell's endocytic machinery, or -- in a more radical proposal -- the proteins may trigger a signaling pathway from their internal location that induces the cell's surface proteins to carry out the sequestering of MHC-1.
Ganem's lab has studied KSHV since its discovery seven years ago, and was the first to successfully grow the virus in culture. In the current research, the UCSF scientists systematically examined a collection of genes that they suspected to play a role in disease induction by the virus. They tested the ability of each of these genes to reduce levels of MHC-1 in cultured cells. This identified two viral genes, called K3 and K5, that reduced MHC-1 proteins at the cell surface by 20- to 30-fold. The two genes are about 40 percent identical to one another, but are not related to any other known genes, they report.
Ganem and Coscoy are now looking at other aspects of immune function that might be modulated by the two virus genes they identified, as well as continuing to search for additional viral proteins that might impair host immunity in other ways.
Until the advent of modern antiretroviral therapies for AIDS, Kaposi's sarcoma was the most common cancer of AIDS patients. Therapies that now control the AIDS virus have also controlled KS, Ganem pointed out, because as patients become less immunodeficient they can better control the replication of KSHV -- despite the ability of KSHV to encode functions like K3 and K5. But when host defenses are somewhat impaired, further immune sabotage by proteins like K3 and K5 can help KSHV spread more widely in the patient and ultimately lead to formation of a tumor.
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