Ever since the discovery last year of a mutant gene that protects HIV-positive people from progressing to outright AIDS, optimism has been mounting as to possible therapeutic payoffs.

That gene, CCR-5, when normal, encodes a chemokine cofactor which, in collusion with the CD4 receptor on the surface of T cells, ushers the virus into its target cell. But some lucky people inherit, from one parent or both, mutated CCR-5 genes that fail to function as the second key to unlock the T cell's door. (See BioWorld Today, Sept. 27, 1996, p. 1.)

Individuals who acquire a double dose of the mutant gene — homozygotes — are virtually protected for life from HIV infection. They are extremely rare in the HIV population; so much so that a gay sailor with a high-risk lifestyle, but no long-term progression to clinical symptoms of AIDS, caused a stir in Australia as the only known patient on record there with two mutant copies of the CCR-5 gene. (See BioWorld Today, March 4, 1997, p. 1.)

Heterozygotes, endowed with only a single dose of the abnormal gene, still benefit by postponement of their overt disease from an average 10 years to 13 or so. Among populations of nonprogressors, they are twice as numerous as those with normal genes.

Drug Discovery Running Into Complications

"There are certainly investigations under way into therapies that take advantage of this finding," observed virologist/immunologist Oren Cohen, at the National Institute of Allergy and Infectious Diseases (NIAID), in Bethesda, Md. "Some groups are attacking the issue by just trying exogenous chemokines, to confer protection on patients who lack that benefit of an abnormal CCR-5 gene."

He continued: "And there are some other pretty ingenious strategies out there. There's a group at Bowman Gray School of Medicine, in Winston-Salem, N.C.,which is designing molecules that will bind to CCR-5 in the cell and prevent it from getting expressed on the cell surface. All of these approaches," Cohen pointed out, "are trying basically to recapitulate the situation of the CCR5 mutation, trying to come up with the same phenotypes by meddling with the system." (See BioWorld Today, June 21, 1996, p. 1.)

But the system is more complicated than merely mutating a single gene to prevent HIV's entry into the immune defenses' key T cells.

Cohen is first author of a paper in the current Journal of Clinical Investigation, dated Sept. 15, 1997. Its self-explanatory title: "Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors." The article's senior author is immunologist Anthony Fauci, director of NIAID.

"This study," Fauci pointed out, "fortifies the concept that HIV long-term nonprogressors represent a diverse group. Multiple immune system factors, genetic and other host factors, and viral factors contribute to the clinical profiles of these patients, who usually have preserved immune function and low levels of HIV in their bodies."

To reach this seminal determination — which partially negates the received wisdom as to mutant CCR-5's prowess — Cohen and his team analyzed blood and lymph-node tissue from 33 HIV-infected patients, 31 homosexual men and two women, who had gone from seven to 12 years without progressing to AIDS.

"For years," Cohen recounted, "we've known that our cohort of nonprogressing patients is quite heterogeneous. Then, with the discovery of the abnormal CCR-5 gene, we said: 'Well, perhaps our long-term nonprogressors who carry one abnormal gene, maybe they're the one's with the highest CD-4 counts and lowest levels of plasma viremia.'

"So, in testing this hypothesis, we expected that we would find a difference when we analyzed our cohort according to their CCR-5 genes. We expected that those who carried the abnormal gene would look better, would have a more favorable profile, than those who had two normal CCR-5 genes. And it wasn't the case.

"When we measured CD4," Cohen told BioWorld Today, "those who had the two normal copies of the gene vs. those who carry one abnormal copy had exactly the same mean CD4 counts, approximately 900.

"And when we looked at the frequency of HIV-infected cells, either in the bloodstream or even in the lymph node," he went on, "there was absolutely no difference. When we looked at levels of virus replication from cells in the lymph node, again, there's heterogeneity within each of the subgroups, and no difference in the mean. In plasma viremia, the same thing."

These contrarian findings, Cohen allowed, do not imply trashing the mutant-gene-oriented drug-discovery efforts. "I think that the large majority of evidence," he said, "would suggest that it is probably a strategy worth pursuing from a therapeutic standpoint."

Widening Search To Other Genes

He added: "I think that right off the bat we're talking about a small subset of individuals. What our test results highlight is that in this unusual situation of long-term nonprogression, there are clearly other protective factors in this group, some of which we have an inkling about, and probably about many of which we have no clue."

Following up on these just-published findings, Cohen and his colleagues at the NIAID laboratory of immunoregulation have begun looking at actual levels of expression of the chemokine receptors in their cohort of long-term nonprogressors.

"We've also been looking for polymorphisms [variant gene copies] in other genes that may be responsible for nonprogressors. Along these lines," he said, "we will report later this month to the meeting in Toronto of ICAAC [Interscience Conference on Antimicrobial Agents and Chemotherapy] a polymorphism in one of the tumor necrosis factor genes, which seems to correlate with levels of plasma viremia in our cohort. That may turn out to be another nonprogression factor." *