Two recent papers report findings about the cancer-causing Kaposi's sarcoma herpesvirus.
In the March 31, 2006, issue of Science, researchers from the National Institutes of Allergy and Infectious Diseases in Bethesda, Md., elucidated how the virus enters cells, while scientists from Mount Sinai School of Medicine in New York reported in the April 6, 2006, issue of Journal of Clinical Investigation on what it does once it gets there.
Kaposi's sarcoma is a cancer caused by a recently discovered herpesvirus called KSHV. Johnan Kaleeba, first author of the Science paper, said that while it is similar to tumor viruses like human papillomavirus in some ways, it also has distinct features. For example, while a biopsy from cervical cancer invariably will contain human papillomavirus, "you don't always find Kaposi's sarcoma herpesvirus around the tumor it has caused," Kaleeba said. In that sense, "cells continue to respond to cellular events caused by the virus" even after the virus itself is long gone.
In the U.S., KHSV's main claim to fame is that it is an opportunistic infection in immunocompromised people, mainly those with HIV infections. A common secondary infection in the early days of the AIDS epidemic, it is not seen very much when HIV infection is well controlled. But in parts of Africa, although sometimes also in the U.S., a more aggressive variant of KSHV disease exists that can spread in people who don't have HIV infection. In those cases, it becomes important - and necessary - to treat the herpesvirus infection directly, rather than relying on it being controlled indirectly through controlling an HIV infection.
Kaposi's sarcoma can infect a variety of cell lines, and Kaleeba and co-author Edward Berger from the NAIAD hypothesized that there must be a specific receptor on target cells that enabled this infection. In their Science paper, they used an assay system to search for such a protein, the same one that Berger's team used a decade ago to identify the first of two co-receptors that HIV needs to enter cells. Basically, the scientists constructed a library of genes encoding the proteins made by a cell line that permits easy entry of KSHV.
By screening the library for the one gene that enabled the viral surface proteins to function as they do during entry, a specific protein called xCT was identified as the cellular entryway for KSHV.
The scientists confirmed their finding by expressing xCT in cells that normally are not susceptible to KSHV infection and found that it did indeed render them vulnerable to the virus. They also showed that antibodies against xCT prevented the virus from entering normally susceptible cells.
The nature of xCT's normal role also might give new insight into KSHV infection and disease. XCT's day job is to transport the amino acid cystine into cells, which is ultimately used to make the cell's main antioxidant, a molecule known as glutathione.
The cell's response to oxidative stress is to want to make more glutathione, so it up-regulates expression of the xCT transporter, and "there are data emerging now indicating that KSHV itself leads to oxidative stress," Berger said.
The logical, though still untested, extension is that "KSHV is facilitating its own replication and dissemination" by causing oxidative stress, which will in turn up-regulate the xCT receptor it then hijacks to enter cells. In relation to people infected with both KSHV and HIV, it is well known that glutathione levels are progressively depleted during HIV disease; since low glutathione triggers xCT expression, "HIV infection may foster KSHV dissemination not only by the obvious effects of immunosuppression, but also by creating conditions that promote up-regulation of the KSHV receptor," Berger said.
In the Journal of Clinical Investigation paper, researchers from the Mount Sinai School of Medicine weighed in on whether another receptor is important in Kaposi's pathogenesis. That one, named viral G-protein coupled receptor, is not on the host cells, but on the virus itself. While transgenic expression of the receptor induces both blood vessel formation and a Kaposi's-like disease in mice, in humans, the receptor is expressed mainly while the virus lyses its host cells and is found in few cells during other parts of the viral life cycle, so how it contributes to Kaposi's progression has been unclear to date.
The authors used a traceable form of viral G-protein coupled receptor to determine that the cells that expressed the receptor were endothelial cells. Next the authors transferred viral G-protein coupled receptor-expressing cells to immune-suppressed mice, resulting in the formation of tumors in the recipients, and observed the accumulation of viral G-protein coupled receptor-expressing cells in lesions over time.
In contrast to previous studies that suggested the receptor induced angioproliferation and tumorigenesis indirectly, through paracrine mechanisms - that is, signals that are secreted by one cell and bind to other cells nearby, the Mount Sinai team's data suggested that viral G-protein coupled receptor promotes angioproliferation directly.
Though the mechanism remains unclear, the scientists speculate that one possibility is autocrine mechanisms - that is, signals that bind to the cell that secretes them.
The scientists give several reasons for their hypothesis but also note that conclusive evidence would depend on comparing the infection caused by normal Kaposi's sarcoma virus to that caused by virus lacking the G-protein coupled receptor - data that will not be forthcoming in the near term, as there is no animal model of Kaposi's sarcoma virus infection.