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"If you consider HIV as being the key, you could say we were able to identify some of the notches in one of the locks on the cell for the HIV key," said Mark A. Goldsmith, MD, PhD.
It has been known through earlier research by other investigators that HIV invades human cells by attaching itself to two receptors on the surface of cells. One binding site is the CD4 receptor. The second is CCR5, a chemokine receptor, which is normally used to bind proteins to the cell.
Scientists had known for some time that the CD4 receptor was a point of entry, but it wasn't until 1996 that it was discovered that, in order to infect humans, HIV needed to bind to a chemokine receptor as well.
"We know that lower mammals like mice don't get infected with HIV," said Israel F. Charo, MD, PhD. "But mice have a CCR5 receptor that is 81 percent identical to the human CCR5 receptor. So we were able to take parts of the human CCR5 receptor and put it on the mouse CCR5. We kept substituting different parts of the human receptor onto the mouse receptor until we found the segments that allowed the mouse cell to become infected with HIV."
The segment of the CCR5 receptor that was most strongly correlated with allowing HIV entry is the amino terminal half of the receptor, particularly those portions of the protein that lie outside the cell surface. The other half of the receptor, called the carboxyl terminal, was less important, Charo said. "Our work shows that multiple segments of the receptor are involved, but the amino terminal end is most important," he said.
In addition to the HIV "key" to the receptor "lock," there is also a chemokine "key" since this is a chemokine receptor, Goldsmith pointed out. "There are notches in the lock for chemokines as well. We found that the HIV and the chemokine notches were not identical," he said. This is a particularly significant finding because it suggests the potential for the development of a drug that could block HIV from binding to the cell without blocking normal chemokine interaction with cells, the researchers said.
"One of the critical goals in drug development is to identify drugs that aren't toxic. If you blocked chemokine interaction with cells, there undoubtedly would be toxicity," Goldsmith said. "Now, in theory, you could target HIV 'notches' on the receptor and block HIV from entering the cell without disruption of the normal functioning of these chemokine receptors."
In another possible application of their work, the researchers suggested the potential for development of a transgenic mouse or rabbit that is genetically altered to have both human CD4 and CCR5. "This would give researchers an animal model that could be used as a new surrogate for humans both to study disease pathogenesis and to test drugs and vaccines for HIV," said Goldsmith.
Goldsmith and Charo and their colleagues publish their findings in the December 13, 1996 issue of Science. Charo is an associate director of the Gladstone Institute of Cardiovascular Disease and a UCSF associate professor of medicine. Goldsmith is an assistant investigator at the Gladstone Institute of Virology and Immunology and a UCSF assistant professor of medicine. Both institutes are affiliated with UC San Francisco and located at San Francisco General Hospital.
This is the first major collaboration between researchers from the two institutes. Charo has been working in chemokine research since the early 1990s, cloning the human MCP1 receptor in 1993 and the CCR5 mouse receptor in 1995. His work has been directed primarily to cardiovascular research whereas Goldsmith has been working in molecular immunology and virology research and was interested early in the role of cell surface receptors and antiviral factors in HIV disease.
"For the Gladstone Institutes this represents an important milestone in terms of inter-institute collaboration and it is an example of synergy between two UCSF-affiliated labs on the SFGH campus," Goldsmith said. The collaboration is an example, the researchers said, of the joining of basic immunology and virology research that is made possible by the support of the Gladstone Institutes. "This project draws from both the chemokine and HIV fields, and has moved forward rapidly because of the wealth of knowledge and reagents available in these two areas. Gladstone support has played a critical role in laying the groundwork for this collaboration," said Charo.
Co-authors of the study are Robert E. Atchison, Gladstone senior research associate; Laura Digilio, MD, postdoctoral fellow, of the Gladstone Institute of Virology and Immunology; and Jennifa Gosling, research associate; Felipe S. Monteclaro, PhD, postdoctoral fellow; and Christian Franci, research associate, of the Gladstone Institute of Cardiovascular Disease.
The Gladstone Institutes are supported by an endowment from the J. David Gladstone Institutes, named for a prominent real estate developer who died in 1971. J. David Gladstone's will created a testamentary trust that reflects his long personal interest in medical research.
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