A sexually active homosexual man in Australia seems to be disproving the recent finding that people who lack the front-line receptor for HIV won't get AIDS.

This individual, now in his early middle years, harbors a double-strength mutation in his gene for the chemokine receptor CCR5, which was identified last year as the HIV co-factor molecule that gives the virus "main entrance' access to the body's immune system. (See BioWorld Today, Sept. 27, 1996, p. 1.)

A brief paper in the just-published March issue of Nature Medicine reports: "HIV-1 infection in an individual homozygous for the CCR5 deletion allele.' That is to say, this HIV-positive Australian subject had inherited from both parents a mutation that deletes a 32-base-pair sequence from his CCR5 gene, thus rendering it helpless to smuggle the HIV into its initial target cells. (See BioWorld Today, Sept. 27, 1996, p. 1.)

Such spayed genes are vanishingly rare in the universe of HIV-infected people. A one-parent mutated copy of the gene slows down such a heterozygous person's progression from initial infection to symptomatic AIDS. Two-copy homozygous individuals are so few and far between that such a person is regarded as essentially immune to AIDS. The Australian. man is the only CCR5 homozygote among 265 HIV-infected patients at Sydney's Westmead Hospital.

Robyn Biti, a pre-doctoral student in immunology/virology at Westmead, is the Nature Medicine paper's first author. "We haven't found any other cases, and we don't know of any reports from elsewhere in the world,' she said.

Yet, her asymptomatic, putatively HIV-proof, patient is not home free.

Despite missing the 32-bp CCR5 gene fragment, he tested HIV-seropositive in 1992, and had transient symptoms of infection. At that time, his CD4 T-cell count was 960 (41 percent of normal). It had dropped by half in November 1996, to 460. "The mode of infection,' the paper noted, "appears to be his homosexual intercourse . . .with multiple partners . . . .'

Despite this high-risk lifestyle, and declining CD4 count, he remains asymptomatic. The question is: For how long?

False Sense Of Security Imperils Safe Sex

On this score, Biti made the point that, rare as the mutation is among HIV-positives, it occurs with high frequency among uninfected homosexuals. "These findings,' she wrote, "have lead to concern that knowledge of their CCR5 genotype amongst such men may lead to cessation of safe sex practices.'

"There's no accounting for this man's failure to escape HIV progression, thanks to his CCR5 mutation. "All we can do is hypothesize,' she observed. "We don't have any evidence to support one theory or another at this stage. One likely cause,' she continued, "might be that for some reason he is using another coreceptor, in place of the one with which he was initially infected. It could be CXCR4 or CCR3,' she speculated, "and we're looking at studies of the latter right now.

"We don't understand why the virus tends to use CCR5 for the initial infection, and not CXCR4 * fusin,' Biti continued. The prime difference between them is that CCR5 ushers HIV into monocyte (macrophage) target cells, whereas fusin opens wide the gates to T cells. (See BioWorld Today, May 13, 1996, p. 1.)

Which leads to an article in today's Proceedings of the National Academy of Science (PNAS), dated March 4, 1997. Its title: "The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes.' Its principal author is Charles Mackay, senior director of immunology at LeukoSite Inc., Cambridge, Mass.

The authors raised monoclonal antibodies to CCR5 and CXCR4, HIV's main wrecking bars for forced entry into its target cells. Then they used those antibodies to map the sites of those receptors on the cells of the immune system.

"CCR5 is the critical receptor for transmission of the virus during the early stages of the disease,' Mackay said.' CXCR4 * fusin * is an important receptor later in the disease progression. It's thought to be a critical event in the so-called Ôcrash' of patients' immune systems.'

He added: "It is extremely important to understand how the virus changes its targets from one set of immune system cells to another. We think that the dramatic drop in T cell numbers in advanced AIDS patients could be due to the virus switching from CCR5 receptors to using fusin instead.

LeukoSite's Two Routes To Drug Discovery

"It's the CCR5 receptor that appears to be rate-limiting,' said Chris Mirabellim, president and CEO of LeukoSite, "because it's the receptor with which the virus begins its infection process. That's consistent with the story that people who don't have that receptor escape that process. If we were able to block CCR5 early on in the infection, it might be a way of treating these patients at very different stages of their disease than we've been treating them up to now.'

In this drug discovery pursuit, LeukoSite is pursuing two separate pathways: "We're working with the Warner-Lambert Co. [of Morris Plains, N. J.], Mirabelli said, "on orally available, small-molecule antagonists of the CCR5 receptor.

"And on our own, LeukoSite is looking at the potential role of monoclonal antibodies in the strategy for blocking receptors. So far, as our PNAS paper reports, we have identified such antibodies, but it's still early in the research phase to make any claims about them. Over the next few months,' he added, "we hope to further characterize these receptors, so we can determine whether or not they might be of value as drug development candidates.' *