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Thursday, Aug. 8, 1996
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New Insights into AIDS-Associated Skin Disease
Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have determined the entire genetic sequence of the virus that causes molluscum contagiosum, a common skin disease that is persistent and sometimes disfiguring in HIV-infected individuals and others with weakened immune systems.
Bernard Moss, M.D., Ph.D., chief of the NIAID Laboratory of Viral Diseases (LVD), and his colleagues from the LVD, the National Library of Medicine and the University of Heidelberg in Germany report their new data on the molluscum contagiosum virus (MCV) in the Aug. 9, 1996 issue of Science.
"These new findings provide insights into the strategies used by MCV to evade the immune system," says Anthony S. Fauci, M.D., NIAID director. "They represent an important step toward developing new treatments and diagnostic tools to help people with molluscum contagiosum."
"Until now, relatively little has been known about MCV because the virus has never been grown in the laboratory, and there is no animal model to study the infection," says Dr. Moss. "With the complete DNA sequence of MCV in hand, it will now be possible, for the first time, to test drugs against the various enzymes and other proteins encoded by MCV genes and to study how the virus protects itself from immune responses."
MCV is transmitted by direct skin contact, and is most often seen among small children and sexually active adults. The virus causes small dome-shaped bumps called papules, three to five millimeters in diameter. In people with healthy immune systems, the papules are usually few in number and generally resolve spontaneously within a few months. Treatment, when needed, is usually akin to that used for warts: freezing, treatment with caustic agents, removal with a sharp instrument or electrocautery.
In people with HIV infection, molluscum contagiosum is often a progressive disease, resistant to treatment. Overall, molluscum contagiosum afflicts an estimated 5 to 18 percent of HIV-infected individuals; as many as 33 percent of HIV-infected people with severely weakened immune systems are affected.
In HIV-infected individuals with relatively intact immune systems, MCV papules are usually few in number, localized to the groin or face. Once an individual's CD4+ T cell count falls below 200 cells per cubic millimeter of blood (mm3), the lesions tend to proliferate and spread. At this stage of HIV disease, a person may have more than 100 papules on the face (including the eyelids), trunk and groin; lesions sometimes coalesce to form giant lesions that measure 1.5 centimeters in diameter. In patients with CD4+ T cell counts lower than 50/mm3, the lesions may extend onto mucosal surfaces of the lips or conjunctiva.
MCV is one of only two poxviruses known to specifically infect people. The other human poxvirus is a distant relative: variola virus, which causes smallpox. (Chickenpox is caused by a herpes virus called varicella zoster virus). Whereas smallpox is a sudden and severe infection that is either quickly controlled by the immune system or results in death, molluscum contagiosum is a slow disease that evokes a minimal immune response.
"Despite being in the same family, variola and MCV have very different strategies of infection," says Dr. Moss. "This suggested to us that their genetic sequences would be quite different -- this proved to be the case -- and that these differences would help explain the differences in the pathogenesis of the two diseases."
In experiments lasting more than a year, the NIAID researchers performed the technically daunting task of sequencing the entire genome of MCV. They then compared the MCV DNA sequences to all known DNA sequences, using the GenBank database of the National Center for Biotechnology Information of the National Library of Medicine.
The researchers found that although MCV uses the same genes as variola for certain cellular processes such as replication and production of the viral particle, it lacks many variola genes thought to be important in interactions with the immune system.
Instead, MCV appears to have its own unique genes that encode proteins that help it to evade immune detection. "It takes a long time before the body becomes aware of MCV infection, a phenomenon that may be explained by a number of MCV genes and their products," says Dr. Moss.
Among the MCV genes, the researchers found several that were very similar to human genes that make cellular proteins with known functions in the immune response. They speculate that three may be especially important to the virus's evasion of the body's defenses:
- a gene that makes defective versions of a cell surface protein -- MHC-I -- that ordinarily marks a virus-infected cell for destruction. The defective MHC-I molecule encoded by the MCV gene may compete with the assembly of normal MHC-I proteins, or trick immune system cells to spare the infected cell. This strategy is used by other viruses, such as cytomegalovirus.
- a gene that makes proteins that compete with or block the action of chemokines, molecules that cause inflammatory cells to come to the site of infection.
- a gene that makes a viral protein that protects the cell from caustic chemicals called peroxides, made by cells to fight infection.
The researchers note that MCV may have other genes important to immune evasion that are presently unknown because their sequences are not similar to known proteins.
Dr. Moss' co-authors include Tatiana G. Senkevich, Ph.D., Joachim J. Bugert, M.D., and Jerry Sisler of the NIAID Laboratory of Viral Diseases; Gholamreza Darai, M.D., of the University of Heidelberg, Germany; and Eugene V. Koonin, Ph.D., of the National Center for Biotechnology Information of the National Library of Medicine (NLM).
NIAID and NLM are components of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
Senkevich TG, et al. Complete genome sequence of a human tumorigenic poxvirus predicts novel host-response evasion genes. Science 1996;273:813-816.
Gottlieb SL, Myskowski PL. Molluscum contagiosum. International Journal of Dermatology 1994;33(7):453-461.
NIAID press releases, fact sheets and other materials are available on the Internet via the NIAID home page. The address is http://www.
niaid.. nih. gov