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

The finding, reported by a team from the Gladstone Instituteof Virology and Immunology at UC San Francisco, suggests apossible target for therapies aimed at preventing thevirus's entry into these tissues and perhaps others, aswell.

The scientists presented their study results yesterday(February 3) at the Sixth Conference on Retroviruses andOpportunistic Infections in Chicago.

HIV-1 generally resides in the blood, infecting the immunesystem's T cells and, to a lesser extent, other immunesystem cells, increasingly compromising the body's abilityto 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 systemcells, some of which are not.

While these tissues are not the principle target of HIVinfection, studies indicate that, when infected, cells inthese tissues may be the underlying cause of some lethalHIV-associated diseases, including HIV-associated dementiaand HIV-associated cardiomyopathy, or death of heart muscle.

There is also concern that cells in these tissues serve asreservoirs of latent or persistent virus that are protectedfrom detection by the immune system, and that these hiddenpools may be less susceptible to the combinations of drugscurrently used to combat HIV infection, known as highlyactive anti-retroviral therapy, or HAART.

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

However, as the disease progresses, the virus often altersits genetic make-up in the blood, and, in so doing, switchesits co-receptor affinity from CCR5 to CXCR4, therebyexpanding the pool of target cells and making it moredifficult to therapeutically block infection.

In the current study, the researchers sought to determinewhether CCR5, already thought to be a predominantco-receptor for mediating HIV infection of brain cells ingeneral, remained predominant as HIV-associated dementiadeveloped, or whether HIV evolved to use other co-receptorsas well. More broadly, the researchers sought insights intowhether co-receptor specificity varied amongst virusesinfecting the various tissues of the body.

Their results were provocative. In an examination of 13brain-derived and six colon-derived viruses, the researchersdetermined that HIV gained entry to cells uniformly andefficiently through the CCR5 co-receptor alone. Some virusesgained entry through several other known co-receptors--CCR3,CCR8 and US28--but when they succeeded, they achieved onlylow levels of infection. No virus recognized several otherknown 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 fortissues rather than blood there is a gateway or selectionpressure to use CCR5 in order to propagate or live," saidStephen Chan, the lead author of the study and an MD/PhDstudent in the laboratory of Mark Goldsmith, MD, PhD, at theUCSF-affiliated Gladstone Institute of Virology andImmunology which is located at San Francisco GeneralHospital Medical Center.

And this finding, he said, bodes well for the effectivenessof drugs (some of which are in development) that could blockthe action of CCR5, as it suggests that tissue-specific HIVwill not evolve to recognize other co-receptors, like CXCR4or CCR3.

"A lot of companies wonder if drugs that block CCR5 willcause tissue-specific viruses to switch co-receptors andbecome resistant. Our study suggests they may not," saidChan.

"All the viruses in the brain and colon that we studied useCCR5 as the main mode of entry. We believe that it is thenecessary mediating factor and that it probably controlsentry into other body tissues, as well."

Because the study demonstrates that HIV uses CCR5 to entercolon tissue, as well as brain tissue from non-dementedpeople, CCR5 can no longer be considered the likely factorleading to the development of HIV-associated dementia.

"There must be factors other than co-receptor selection thatare responsible for the development of HIV-associateddementia," said Chan. "And these events might be happeningafter the virus infects cells, rather than during theinfection process itself."

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

Funding for this study was provided by the J. DavidGladstone Institutes and Pfizer Inc.

The Gladstone Institute of Virology and Immunology, foundedin 1991, focuses its research on HIV and AIDS. The Instituteis one of three that make up the J. David GladstoneInstitutes, a private biomedical research instituteaffiliated with UCSF and named for a prominent real estatedeveloper who died in 1971. His will created a testamentarytrust that reflects his long-standing interest in medicaleducation and research.