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UCSF/Gladstone Finding May Explain HIV'S Ability To Infect Cells Lacking The Key Target Of HIV: The CD4 Receptor

e culture experiments. The answer was yes, determined by substituting a recombinant protein containing solely this extra-cellular portion of CD4 (provided by collaborators at SmithKline Beecham) for the CD4-positive cells.

When the CCR5-bearing cell was mixed with the soluble CD4 (sCD4) protein, the researchers found clear evidence of infection. "A functional receptor complex was generated, indicating that the complex could be formed without CD4 being anchored in a particular cell membrane," said Goldsmith.

All that mattered was that the outside portion of the CD4 molecule be available in close proximity to the co-receptor-bearing cell.

"With further studies, we even showed that it required only a small fragment of the outside portion of CD4, known as the D1 domain. Apparently, CD4, or even just a portion of it, when juxtaposed with the co-receptor on a target cell, can reconstitute a full permissive system," he said.

The researchers suspect that the extra-cellular portion of CD4, the "ectodomain," may be physically juxtaposed with CCR5 on these CD4-negative cells, and that virus floating by may see this physical interaction as a single receptor complex.

"It may be that HIV doesn't have any way of realizing that these receptors are actually on different cells," said Goldsmith. It appears to be yet another devious pathway by which HIV further insinuates itself into the host."

An important step the researchers hope to take is to determine what types of cells in humans can cooperate in this way, said Goldsmith. "We did one such research effort using human brain cells in laboratory cultures, and found that the system did work, giving us compelling evidence that this pathway might be applicable during typical infections of the brain."

Co-authors of the study were Roberto Speck, MD; Ursula Esser, PhD; Michael L. Penn, BA; Daniel A. Eckstein, BA, and Stephen Chan, BA, from the UCSF-affiliated Gladstone Institute of Virology and Immunolo
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Contact: Jennifer O'Brien
jobrien@itsa.ucsf.edu
415-476-2557
University of California - San Francisco
5-Feb-1999


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