Researchers Identify Molecular Site That Is Key To HIV's Ability To Infect Cells Of Brain, Colon

February 05, 1999

Researchers have determined that HIV infects cells of the brain and colon by binding with a particular co-receptor, CCR5, located on the surface of some, but not all, cells targeted by HIV.

The finding, reported by a team from the Gladstone Institute of Virology and Immunology at UC San Francisco, suggests a possible target for therapies aimed at preventing the virus's entry into these tissues and perhaps others, as well. The scientists presented their study results yesterday (February 3) at the Sixth Conference on Retroviruses and Opportunistic Infections in Chicago.

HIV-1 generally resides in the blood, infecting the immune system's T cells and, to a lesser extent, other immune system cells, increasingly compromising the body's ability to respond to opportunistic infections.

However, HIV also migrates from the blood into tissues, infecting various types of cells in the brain, colon, testes, ovaries and heart, some of which are immune system cells, some of which are not.

While these tissues are not the principle target of HIV infection, studies indicate that, when infected, cells in these tissues may be the underlying cause of some lethal HIV-associated diseases, including HIV-associated dementia and

HIV-associated cardiomyopathy, or death of heart muscle. There is also concern that cells in these tissues serve as reservoirs of latent or persistent virus that are protected from detection by the immune system, and that these hidden pools may be less susceptible to the combinations of drugs currently used to combat HIV infection, known as highly active anti-retroviral therapy, or HAART.

HIV generally initiates infection in the body by latching first onto the CD4 receptor, the loading dock on the target cell's surface, and then onto a co-receptor, normally CCR5, which is also located on the cell's surface. The multi-step binding process culminates when HIV fuses with the cell.

However, as the disease progresses, the virus often alters its genetic make-up in the blood, and, in so doing, switches its co-receptor affinity from CCR5 to CXCR4, thereby expanding the pool of target cells and making it more difficult to therapeutically block infection.

In the current study, the researchers sought to determine whether CCR5, already thought to be a predominant co-receptor for mediating HIV infection of brain cells in general, remained predominant as HIV-associated dementia developed, or whether HIV evolved to use other co-receptors as well. More broadly, the researchers sought insights into whether co-receptor specificity varied amongst viruses infecting the various tissues of the body.

Their results were provocative. In an examination of 13 brain-derived and six colon-derived viruses, the researchers determined that HIV gained entry to cells uniformly and efficiently through the CCR5 co-receptor alone. Some viruses gained entry through several other known co-receptors--CCR3, CCR8 and US28--but when they succeeded, they achieved only low levels of infection. No virus recognized several other known co-receptors thought to be important in HIV disease, including CXCR4, BOB/GPR15 or Bonzo/STRL33.

"It seems likely that in these viruses that are specific for tissues rather than blood there is a gateway or selection pressure to use CCR5 in order to propagate or live," said Stephen Chan, the lead author of the study and an MD/PhD student in the laboratory of Mark Goldsmith, MD, PhD, at the UCSF-affiliated Gladstone Institute of Virology and Immunology which is located at San Francisco General Hospital Medical Center.

And this finding, he said, bodes well for the effectiveness of drugs (some of which are in development) that could block the action of CCR5, as it suggests that tissue-specific HIV will not evolve to recognize other co-receptors, like CXCR4 or CCR3.

"A lot of companies wonder if drugs that block CCR5 will cause tissue-specific viruses to switch co-receptors and become resistant. Our study suggests they may not," said Chan.

"All the viruses in the brain and colon that we studied use CCR5 as the main mode of entry. We believe that it is the necessary mediating factor and that it probably controls entry into other body tissues, as well."

Because the study demonstrates that HIV uses CCR5 to enter colon tissue, as well as brain tissue from non-demented people, CCR5 can no longer be considered the likely factor leading to the development of HIV-associated dementia.

"There must be factors other than co-receptor selection that are responsible for the development of HIV-associated dementia," said Chan. "And these events might be happening after the virus infects cells, rather than during the infection process itself."

Co-authors of the study included Roberto Speck, MD, Sarah Gaffen, PhD, and Mark A. Goldsmith, MD, PhD, of the Gladstone Institute of Virology and Immunology at UCSF; Christopher Power, MD, of the University of Calgary; and Bruce Chesebro, MD, at the Lab of Persistent Viral Diseases, Rocky Mountain Labs, National Institute of Allergy of Infectious Disease.

Funding for this study was provided by the J. David Gladstone Institutes and Pfizer Inc.
-end-
The Gladstone Institute of Virology and Immunology, founded in 1991, focuses its research on HIV and AIDS. The Institute is one of three that make up the J. David Gladstone Institutes, a private biomedical research institute affiliated with UCSF and named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing interest in medical education and research.



University of California - San Francisco

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