It came as a surprise two years ago that the AIDS virus has a hidden accomplice in the human body it's invading. This CXCR4 chemokine receptor, a.k.a. fusin, hands HIV the keys to the kingdom, allowing the pathogen to break and enter the cells targeted for infection.
"Once CXCR4 was recognized as a co-receptor for HIV," recalled immunologist Richard Horuk, "several things happened. The whole HIV research field joined with the immunologists and concentrated on chemokines," he said. (See BioWorld Today, Nov. 14, 1996, p. 1, and Feb. 2, 1997, p. 1.)
Horuk, a senior scientist at Berlex Biosciences, in Richmond, Calif., told BioWorld Today, "There's been a massive explosion of activity in the whole area for the past two years, which has led to major advances in recognizing the role of these molecular moles."
Two of those advances appear in today's issue of Nature, dated June 11, 1998.
The first paper, from a consortium of academic researchers in Japan, bears the title, "The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract."
The second article's title is "Function of the chemokine receptor CXCR4 in hematopoiesis [blood-cell formation] and in cerebellar development." Its senior author is molecular immunologist Dan Littman, at New York University. (See BioWorld Today, July 18, 1997, p. 1.)
Horuk, who wrote an editorial accompanying these two Nature papers, summed them up: "They report that deletion of the CXCR4 gene is embryologically lethal in mice, producing a multiplicity of effects, including serious developmental defects in the immune, circulatory and central nervous systems. These studies expand the biological importance of chemokines from that of simple immune modulators to a much broader biological role than was at first appreciated."
Evidently, CXCR4's day job in the body is more varied than its moonlighting for HIV.
"CXCR4," Horuk pointed out, "appears to be expressed on almost every cell in the body you could look at." On every cell surface, it acts as a receptor for a ligand called stromal derived factor (SDF).
"SDF is a major chemoattractant," Horuk observed. "It chemoattracts T cells and brain neurons, for example, as we at Berlex have shown. It's particularly important during fetal development," he added, "and Littman's work highlights that."
That work showed that fetal transgenic mice lacking the CXCR4 gene suffered the same defects of blood-vessel and heart formation as other transgenics deprived of SDF. This indicated that their respective gene products act as a pair, with CXCR4 presumably the sole receptor for the ligand.
AIDS Dementia Connection Doubtful
Littman and his co-authors also found that development of the brain's cerebellum is strikingly abnormal in the mutant mice. "These results," his paper remarked, "may be important for designing strategies to block HIV entry into cells and for understanding mechanisms of pathogenesis in AIDS dementia."
However, Littman told BioWorld Today, "It's too early to speculate on this in any intelligent way. We don't really know if these molecules are playing an important role in the pathogenesis in the brain, in AIDS. It might make some sense, but the fact is that CXCR4 itself, its usage by viruses, doesn't correlate terribly well with the onset of AIDS dementia."
He added: "People who have AIDS dementia don't generally have viruses . . . in the brain."
As for therapies based on inhibiting the CXCR4 chemokine, Littman said, "It's possible, even probable, that taking CXCR4 away after fetal development has been completed is not going to do terribly much damage. And we're trying to find that out."
This observation derives from the presumption that the chemokine shuts down after birth, and reemerges only as an HIV co-conspirator. But as Littman pointed out, the receptor may have other essential functions in the adult body.
"In terms of development in the brain," he went on, "most of that is completed early on in life, so it's conceivable that CXCR4 inhibition would not have any effect there. Drugs could be developed that don't pass the blood-brain barrier, so it may not be such an issue.
"CXCR4 might still be involved in generating B lymphocytes," he said, "or migration of white blood cells within the body. It's possible that taking it away by impeding, or blocking it by using anti-HIV drugs, may interfere with the migration of leukocytes.
"Whether it has an effect on vascularization later on in life," Littman remarked, "is anybody's guess. For all we know, it might even be an anti-tumor drug."
Blocking CXCR4 A Dicey Drug-Discovery Project
"Clearly, " he concluded, "we need to do experiments that are much more finely tuned to inactivate the gene after completion of development. We have the tools to do that now."
Horuk commented that "Littman's blocking scenario may be true, but I think one has to be a little more cautious. If you were to aim a small molecule at CXCR4 that affected the fetus, I would predict you'd have severe problems, based on these two studies.
"If you did this in an adult," he continued, "I'm not sure you would see anything adverse, because what we see here is a role for this receptor in development. When you're already developed, I fail to see how that could have adverse effects.
"I think the other thing that Littman was alluding to," Horuk continued, "is that people in the HIV field were very worried about the fact that if you initiated a drug therapy to block another HIV co-factor, CCR5, which acts on growth early in gestation, would you now switch the virus to the more lethal late-stage CXCR4 phenotype, and accelerate the demise of the individual, by progressing to a much more rapid form of the disease?
"The evidence suggests that's not the case," Horuk went on, "so many companies — including my company, Berlex — have drug-discovery programs looking for small-molecule inhibitors of chemokine receptors." *