|Landmark Discovery of a Kaposiís Sarcoma-Associated Herpesvirus
Receptor Provides New Perspectives on Disease Associated with HIV/AIDS
Researchers at the National Institute of Allergy and Infectious Disease (NIAID),
a component of the National Institutes of Health (NIH), have identified a critical
human cell surface molecule involved in infection by Kaposiís sarcoma herpesvirus
(KSHV), the virus that causes Kaposiís sarcoma and certain forms of lymphoma.
Kaposiís sarcoma is a major cancer associated with HIV/AIDS, and it typically
manifests as multiple purple-hued skin lesions.
In the March 31, 2006 issue of Science, NIAID research fellow Johnan Kaleeba,
Ph.D. and senior investigator Edward A. Berger; Ph.D., describe 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 Kaposiís sarcoma and other syndromes associated
with the virus.
The natural function of xCT in the body is to transport molecules necessary
for protecting against stress into cells. When cells are stressed, they express
more xCT on their surfaces. Of note, this sort of stress can be caused by KSHV
itself. This suggests 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.
ďThe advancement of knowledge achieved in this study highlights the outstanding
intramural research that takes place here on the NIH campus,Ē says Elias A. Zerhouni,
M.D., NIH director.
ďUnderstanding the mechanisms of cell entry of Kaposiís sarcoma herpesvirus
is a landmark achievement in and of itself,Ē says NIAID director Anthony S. Fauci,
M.D. ďBut the connection between the virus and expression of its own receptor
on a cell is even more provocative because it might change the way we think about
KSHV-associated diseases and their treatment.Ē
Although less common in the United States now than early in the AIDS pandemic,
Kaposiís sarcoma is still the most common cancer associated with HIV infection.
Prior to the AIDS pandemic, it was an obscure disease. First identified as a
multi-pigmented skin disease by a Hungarian doctor named Moritz Kaposi in 1872,
it was considered to be quite rare — a medical curiosity usually found
in particular populations such as older Italian men, transplant patients and
young men in certain parts of sub-Saharan Africa. But then at the dawn of the
AIDS pandemic in the early 1980s, the small purplish Kaposiís sarcoma skin lesions
began appearing on the bodies of young American men, many of whom went on to
develop opportunistic infections.
Dr. 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 Dr. Bergerís group
and several other research teams of CCR5 as the other HIV coreceptor.
By applying the same technology used to identify CXCR4, Drs. Kaleeba and Berger
ultimately identified the protein xCT as the receptor that can make cells permissive
for KSHV fusion.
The NIAID discovery may lead to new avenues for treating KSHV, says Dr. Berger.
Moreover, their finding 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 Kaposiís sarcoma.
ďOur finding provides a new perspective on the disease,Ē says Dr. Kaleeba, who
is originally from Uganda where Kaposiís sarcoma accounts for at least 10 percent
of known tumors. ďHopefully 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.Ē
||This illustration shows
how KSHV fuses to and enters a human cell after binding to the protein
News releases, fact sheets and other NIAID-related materials are available on
the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID supports
basic and applied research to prevent, diagnose and treat infectious diseases
such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports
research on basic immunology, transplantation and immune-related disorders,
including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.