Scientists Find New HIV Receptor

By LAWRENCE K. ALTMAN

Published: February 11, 2008

SAN FRANCISCO — Government scientists have discovered a new way that H.I.V. attacks human cells, an advance that could provide fresh avenues for the development of additional therapies to stop AIDS, they reported on Sunday. The discovery is the identification of a new human receptor for H.I.V. The receptor helps guide the virus to the gut after it gains entry to the body, where it begins its relentless attack on the immune system.

The findings were reported online Sunday in the journal Nature Immunology by a team headed by Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases. For years, scientists have known that H.I.V. rapidly invades the lymph nodes and lymph tissues that are abundant throughout the gut, or intestines. The gut becomes the prime site for replication of H.I.V., and the virus then goes on to deplete the lymph tissue of the key CD4 H.I.V.-fighting immune cells. That situation occurs in all H.I.V.-infected individuals, whether they acquired the virus through sexual intercourse, blood transfusions, blood contamination of needles and syringes, or in passage through the birth canal or drinking breast milk. The findings appear to provide some, if not the main, answers to how and why that situation occurs.

Dr. Warner C. Greene, an AIDS expert and the director of the Gladstone Institute of Virology and Immunology here who was not involved in the research, said the findings were “an important advance in the field.” “They begin to shed light on the mysterious process on why the virus preferentially grows in the gut,” Dr. Greene said in an interview. Dr. Fauci, James Arthos, Claudia Cicala, Elena Martinelli and their colleagues showed that a molecule, integrin alpha-4 beta-7, which naturally directs immune cells to the gut, is also a receptor for H.I.V. A protein on the virus’s envelope, or outer shell, sticks to a molecule in the receptor that is linked specifically to the way CD4 cells home in on the gut, the researchers said.

Binding of the virus to the integrin alpha-4 beta 7 molecule stimulates activation of another molecule, LFA-1, which plays a crucial role in the spread of the virus from one cell to another. The actions ultimately lead to destruction of lymph tissue, particularly in the gut. Several other receptor sites for H.I.V. are known. The most important is the CD4 molecule on certain immune cells; the molecule’s role as an H.I.V. receptor was identified in 1984.

Two other important receptors, known as CCR5 and CXCR4, were identified in 1996. CCR5 is a normal component of human cells and acts as a doorway for the entry of H.I.V. People who lack it because of a genetic mutation rarely become infected even if they have been exposed to H.I.V. repeatedly.

“The work we did took nearly two years, and there’s little doubt that what we have found is a new receptor,” Dr. Fauci said in an interview after giving a lecture here, adding that “we certainly have to learn a lot more about it.” Scientists have sought to identify receptors because they offer targets for the development of new classes of drugs.

For example, last year the Food and Drug Administration approved for AIDS treatment a Pfizer drug, Selzentry or maraviroc, which works by blocking CCR5. Dr. Fauci said he hoped his team’s findings would encourage other scientists from different disciplines to explore new ways to attack H.I.V. A number of experimental drugs that block the integrin alpha-4 beta-7 receptor are being tested for the treatment of autoimmune disorders. Dr. Fauci said such drugs should also be studied for their potential benefit in AIDS treatment. Organization of new trials in the next year or so could test such drugs in animals and humans to determine their safety and effectiveness against H.I.V., Dr. Fauci said.

One candidate is a drug, Tysabri or natalizumab, that is marketed for treatment of multiple sclerosis, Dr. Fauci said. Biogen/Elan makes Tysabri. If trials for H.I.V. are successful, Dr. Fauci said, the drugs could be added to existing treatment regimens.