New KS-associated herpesvirus receptor facilitates infectivity and dissemination

June 2006

Researchers have identified a critical human cell surface molecule involved in infection by Kaposi’s sarcoma herpesvirus (KSHV), the virus that causes Kaposi’s sarcoma and certain forms of lymphoma.

Research fellow John-an Kaleeba, PhD, and senior investigator Edward A. Berger, PhD, both of the National Institute of Allergy and Infectious Diseases (NIAID) recently described how the molecule xCT is a major gateway that KSHV uses to enter human cells. The molecule may also play a role in the development of Kaposi’s sarcoma (KS) and other syndromes associated with the virus, according to the study, recently published in Science.

The role of xCT

The natural function of xCT in the body is to transport molecules necessary for protecting against stress into cells, according to a NIAID press statement. When cells are stressed, they express more xCT on their surfaces. This stress can be caused by KSHV itself, suggesting that the virus may facilitate its own infectivity and dissemination in the body by inducing a physiological state that results in increased numbers of its own receptor.

Although less common in the United States now than early in the AIDS pandemic, KS is still the most common cancer associated with HIV infection. Prior to the AIDS pandemic, it was an obscure disease. First identified as a multipigmented skin disease by a Hungarian doctor named Moritz Kaposi in 1872, it was quite rare and only found in certain populations, such as older Italian men, transplant patients and young men in certain parts of sub-Saharan Africa. But in the early 1980s, the small purplish KS lesions began appearing on the skin of young American men, many of whom went on to develop opportunistic infections. (See EI Stories).

Identifying xCT

Berger became interested in KSHV because of his interest in how viruses enter cells. A decade ago, his research team was the first to identify CXCR4 as one of the coreceptors that allows HIV to gain entry into cells of the immune system. This discovery quickly led to the identification by Berger’s group and several other research teams of CCR5 as the other HIV coreceptor, according to a press statement from NIAID.

By applying the same technology used to identify CXCR4, Kaleeba and Berger ultimately identified the protein xCT as the receptor that can make cells permissive for KSHV fusion.

Future considerations

The NIAID discovery may lead to new avenues for treating KSHV, said Berger in the statement. Moreover, the findings should enable scientists to determine whether levels of xCT determine disease severity. It also will allow researchers to study whether the expression of xCT on cells varies among different groups of people and whether these variations are genetic or environmental. This research may ultimately explain why certain groups are more at risk for KS.

“Our finding provides a new perspective on the disease,” said Kaleeba, who is originally from Uganda where Kaposi’s sarcoma accounts for at least 10% of known tumors.

“Hopefully this will be the beginning of exciting new directions in this field, as it is likely to provide a useful framework for integration of the cell biology and epidemiology of this clinically important virus,” Kaleeba said.

For more information:

• Kaleeba JA, Berger EA. Kaposi’s sarcoma-associated herpesvirus fusion-entry receptor: cystine transporter xCT. Science. 2006;311;1921-1924.