Now there are six — and still counting.

Until early last year, AIDS virologists and immunologists assumed that HIV's one and only access to its target macrophages and T lymphocytes was the CD4 receptor that adorned those cells' surfaces.

Then in 1996, a wave of discoveries revealed that the virus also needed, and used, at least three co-factor molecules to break and enter its targeted cells. They labeled these chemokine co-receptors CCR3, CXCR4 (initially "fusin") and CCR5. (See BioWorld Today, Feb. 2, 1997, p. 1 and Nov. 14, 1996, p. 1.)

These chemokine co-receptors, major players in the deadly AIDS game, bear acronymic names that resemble license-plate numbers. ("CC" stands for two linked cysteine amino acids.) And like a baseball card, you can't tell the players without a program, to wit:

CD4: The original HIV receptor, perched atop T lymphocytes and monocytes/macrophages.

CXCR4: The first HIV co-receptor found after CD4, this T-cell-targeting co-factor at first answered to the name of "fusin," because it brokered the fusion of the HIV virion's envelope with the membrane of target cells, enabling entry of the infective retrovirus.

CCR5: This key HIV co-receptor in viral transmission and infection zeros in on macrophages and lymphocytes; belongs to same gene family as CXCR4.

CCR3: Mercifully, the rarest HIV co-receptor yet found. It occurs on certain brain cells incident to AIDS dementia.

That was then.

Now, the current issue of Nature, dated July 17, 1997, announces in two separate articles two new co-conspiring molecular agents for smuggling HIV into its cellular victims.

One paper, by molecular immunologist Dan Littman and co-authors at New York University (NYU), is titled: "Expression cloning of new receptors using simian and human immunodeficiency viruses."

The other, "A new SIV co-receptor, STRL33," is by molecular immunologist Joshua Farber and his associates at the National Institute of Allergy and Infectious Diseases (NIAID), in Bethesda, Md., where fusin was discovered

These latest reports bring to six the number of treasonous gatekeepers now known to yield up to HIV attack the points of entry on cells marked for HIV infection.

Two Centers Announce Same New Co-Receptor

Littman and Farber separately tracked down these latest HIV co-receptors by means of clues akin to Sherlock Holmes' perception that "the dog did nothing in the nighttime." That is, they latched on to the fifth and sixth molecules because they were missing.

"Mouse cells," Littman told BioWorld Today, "are not infectable with HIV or SIV [simian immunodeficiency virus], even if you put CD4 receptors into their culture. So we knew that something else, another receptor, had to be missing."

Whereupon, Littman and his team applied an in vitro retroviral vector cloning approach they had developed over the past eight years, "precisely to be able to do expression cloning of additional receptors."

They took advantage of the fact that "certain species of monkey, like the Rhesus macaque, when infected with SIV develop a disease very similar to human AIDS," Littman continued. "Monkeys that are infected and get sick don't seem to have virus in them that uses CXCR4 [fusin]. So we thought there might be a co-receptor other than fusin that these monkeys might be using."

To their surprise, they found that "all the SIV in their macaques made use of two new chemokine receptors to force viral entry into their simian target cells.

Littman and his lab workers, as an in-joke, informally dubbed these two new co-receptors "Bonzo" and "BOB." The former appellation, Littman explained, recalls a string of old movies that featured a famous chimpanzee named Bonzo. And BOB stands for "Bonzo's brother."

Bonzo, A Temporary Primatological Misnomer

He recalled that one of the peer reviewers of their paper in Nature pointed out that "obviously the NYU authors are not primatologists, because Bonzo was a chimp, whereas they cloned receptors for macaque monkeys."

Littman allowed that soon these vanity-license-plate-like monikers will be replaced by conventional name tags. "I'm almost sure," he observed, "that they have chemokines as ligands, so they will probably be called CCCR-something."

Some such may already have happened, in a sense, with Bonzo. Farber at NIAID discovered the identical co-receptor, and designated it STRL33. This, he told BioWorld Today, stands for "seven-transmembrane domain receptors from lymphocytes."

It was pure coincidence, Farber observed, that NIAID and NYU simultaneously reported STRL33/Bonzo in Nature. "We really had this receptor for quite a while," he explained, "while hunting receptors independently of the HIV story. We didn't know that both theirs and ours were the same."

In their analysis of the two new co-receptors, the NYU group found BOB messenger RNA highly expressed in the human colon. "It will therefore be important to determine," their Nature paper observes, "whether this expression pattern is relevant for sexual transmission of HIV."

As for being able to carry over monkey data into the human condition, Littman made the point: "Part of the reason we went after Bonzo and BOB in the macaques was thinking that they might be the equivalent of the CXCR4 in humans. That we might then be able to extrapolate what we learned from the monkeys to people. Whether we can really make that jump at this point is not clear."

Another question that is far from clear concerns the consequences of seeking drugs to inhibit any of these new HIV co-receptors.

"I've been talking with a lot of people in the pharmaceutical and biotechnology industries since these receptor connections came up a little over a year ago," Littman said. "And I learned that most of the companies in this business have very active programs, trying to interfere with chemokine receptor function.

"A major hope for all of us," he continued, "was that just by blocking CCR5, it would be possible to block transmission of the virus early on, when most of it is CCR5-tropic, and thus be able to limit its spread.

"But now that we know there are so many other receptors that can be used — there may even be additional ones — you have to worry that just by inhibiting CCR5 you're just going to select for viruses that can use these other receptors. We know that if you block CCR5, it's unlikely that would be deleterious, because there are people who are CCR5-negative and seem to be perfectly healthy. But we don't know yet what the normal functions of these other receptors are, or what blocking them might do.

"I'm sure there are more HIV co-receptors out there, waiting to be discovered," Littman said. For HIV-1, we can't be certain. I know there must be an additional one for HIV-2, just based on its pattern of cell infections. There are cells infected by HIV-2 that don't have any of these receptors that we know about. So I'm convinced there are going to be additional ones," he concluded, "and we are looking for them, using the same expression-cloning approach."

Molecular virologist Joseph Sidroski, of Harvard Medical School, will report on his identification of a seventh and eighth viral co-receptor in the August Journal of Experimental Medicine. "GPR1 and GPR15," Sidroski told BioWorld Today, "existed in the database. What we discovered was that they could be used by SIV as co-receptors." *