Researchers from two collaborating laboratories at the National Institute of Allergy and Infectious Diseases (NIAID) have found that the strains of HIV most often transmitted from person-to-person require a cell surface molecule called CC CKR5, in addition to the primary receptor, the CD4 molecule, in order to fuse with the membranes of immune system cells. Fusion is an integral step in the process whereby HIV enters cells.
The current report, from the laboratories of Edward A. Berger, Ph.D., and Philip M. Murphy, M.D., will appear in the June 28, 1996 Science. The paper complements a recent NIAID study that identified another fusion cofactor -- fusin -- used by other strains of HIV for entry into immune cells (see Science May 10, 1996). "These and related studies show the rapid progress that can be made with a continuing investment in basic research," says Department of Health and Human Services Secretary Donna E. Shalala. "The science is moving rapidly, providing potential new targets for the development of drugs and other interventions."
The editors of Science have moved the embargo date and time of the current paper forward, to Wednesday, June 19 at 4:00 p.m. ET, to coincide with the publication of two related papers by independent groups in the June 20 Nature.
In their experiments, the NIAID investigators found that "macrophage-tropic" isolates of HIV-1 fused readily with cells that have both CD4 and CC CKR5 on their surfaces, whereas the same viral isolates failed to fuse with cells expressing only CD4. Macrophage-tropic isolates of HIV-1 preferentially infect macrophages in cell culture experiments. These isolates are the main strains found in patients during the symptom-free stage of HIV disease, which may last for many years.
Previously, Dr. Berger and his group demonstrated that fusin acts as a cofactor for the entry of T-cell line-tropic HIV-1 isolates into immune system cells; these strains tend to appear later in infected people, coincident with the decline of the immune system.
Together with the recent identification by the Berger group of the receptor for T cell-tropic strains of HIV-1, the current identification of CC CKR5 as the receptor for macrophage-tropic strains of HIV adds considerably to our understanding of the mechanisms whereby HIV infects its target cells," comments Anthony S. Fauci, M.D., NIAID director. "This information should prove extremely useful in the delineation of pathogenesis of HIV infection and should serve as a basis for designing new therapeutic strategies."
In addition to its role in fusion, CC CKR5 is a receptor for certain immune-signaling molecules -- RANTES, MIP-1alpha and MIP-1beta -- that are known to suppress HIV infection of cells. These three molecules belong to a family of molecules called chemokines involved in the body's inflammatory response.
When considered with recent data from other groups, our new findings suggest that one mechanism by which RANTES, MIP-1alpha and MIP-1beta suppress HIV infectivity is by blocking the process of fusion used by the virus to enter cells," says Dr. Berger.
The researchers note that other groups have suggested that chemokines might be used therapeutically. "These new data provide a molecular explanation for the suppression of HIV infectivity by chemokines, and suggest that fusion cofactors may provide a potential target for rational drug design," says Dr. Murphy.
The new papers on chemokines and fusion cofactors raise intriguing questions about the wide variation in the natural history of HIV disease in different individuals, the investigators note. For instance, does an abundance of RANTES, MIP-1alpha or MIP-1beta, or a relative lack of functional CC CKR5 and related molecules, explain why some individuals have not become infected with HIV, despite repeated exposure to the virus? A number of NIAID-supported groups are working to answer this and other important questions.
The identification of two fusion cofactors suggests an immediate practical application: the production of a small animal model for study of HIV-1 infection. Such a model would be a potentially valuable tool for developing anti-HIV drugs and vaccines.
"Transgenic animals expressing human CD4 have been developed, but they support HIV-1 replication poorly," explains Dr. Berger. "Transgenic animals expressing fusin and CC CKR5 in addition to CD4 may be more useful."
Dr. Berger is chief of the molecular structure section of NIAID's Laboratory of Viral Diseases (LVD); Dr. Murphy is a senior investigator in NIAID's Laboratory of Host Defenses (LHD). Their co-authors include, from the LVD, Ghalib Alkhatib, Ph.D., Yu Feng, Ph.D., Christopher C. Broder, Ph.D., and Paul Kennedy; and Christophe Combadiere, Ph.D., of the LHD.
NIAID is a component 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.
Reference:Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PM, Murphy PM, Berger EA. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as fusion cofactor for macrophage-tropic HIV-1. Science (June 28, 1996).