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

February 05, 1999

Researchers may have identified the molecular mechanism that enables HIV to cast its infectious net beyond those cells bearing the CD4 receptor, the loading dock that HIV normally first engages on a cell's surface.

The finding was presented earlier this week (February 1) at the Sixth Conference on Retroviruses and Opportunistic Infections in Chicago, by scientists from the Gladstone Institute of Virology and Immunology at UC San Francisco.

In their study, the investigators discovered that cells bearing the CD4 receptor sometimes interact with neighboring cells that lack the CD4 receptor but do bear a "co-receptor," or secondary loading site, such as CCR5 or CXCR4. Together, these proteins create a receptor complex that HIV recognizes as a single unit.

"This so-called `trans' mechanism expands the range of potential cellular targets for HIV-1," said the senior author of the study, Mark A. Goldsmith, MD, PhD, UCSF assistant professor of medicine at the Gladstone Institute.

It also suggests a possible new focus for drug therapies aimed at preventing the spread of HIV to non-CD4 receptor cells. "We still need to demonstrate this in rodent models," said Goldsmith, "but this is an intriguing start." HIV generally infects the immune system's T-cells, which reside in the blood, latching first onto the CD4 receptor and then onto the CCR5 co-receptor located on the same cell's surface. The multi-step binding process culminates with HIV's fusion with the cell.

However, the virus also migrates from the blood into tissues, infecting various types of cells in the brain, colon, testes, ovaries and heart. Some of these cells are immune system cells, some are not. Many are CD4-negative cells, such as cell's bearing CD8 receptors in lymphoid tissues; astrocytes and endothelial cells in the brain; epithelial cells in the colon; and myocytes in heart tissue.

While CD4-negative cells are not the principle target of HIV infection, studies indicate that these cells, when infected, may be the underlying cause of some lethal HIV-associated diseases, including HIV-associated dementia and HIV-associated cardiomyopathy, or death of heart muscle.

Moreover, there is concern that reservoirs of latent or persistent virus may reside in cells that are protected from detection by the immune system, and that these hidden pools of virus may be less susceptible to the combinations of drugs currently used to combat HIV infection, known as highly active anti-retroviral therapy, or HAART.

CD4-negative cells, said Goldsmith, may be more apt to harbor sequestered HIV than CD4-positive cells, as the latter circulate in the blood and are fairly susceptible to HAART therapy.

To determine how HIV infects CD4-negative cells, the researchers developed a culture system in which various CD4-positive cells lacking the CCR5 receptor were mixed with CD4-negative cells expressing CCR5. Then, after verifying that neither cell type alone could be infected, the researchers exposed the cells to strains of HIV that are known to use CCR5 as a co-receptor.

The result, infection of both cell types, indicated that cooperative interaction between the co-mingled cell types could create an effective viral receptor complex.

"We observed that the CD4 receptor and a co-receptor do not need to be displayed together on target cell surfaces to be engaged by HIV, and that they can cooperate as an effective viral receptor complex," said Goldsmith. The team determined that successful infection depended on the presence of both CD4 and CCR5 (or CXCR4, another co-receptor that is sometimes used by HIV), and required physical proximity of the cells.

The researchers subsequently carried out tests aimed at documenting, and pinpointing, the underlying molecular interaction.

In doing so, they sought to determine whether the extra-cellular portion of CD4, in the form of soluble CD4, was itself sufficient to represent the CD4-positive cell in these 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 Immunology, which is located at San Francisco General Hospital Medical Center; Lynn Pulliam from the San Francisco Veterans Affairs Medical Center; and Raymond Sweet from SmithKline Beecham. Funding for this study was provided by the J. David Gladstone Institutes and the California University wide AIDS Research Program ( ).
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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