If 1996 was the year of anti-HIV-1 triple-drug therapy, 1997 marked the emergence of chemokine coreceptors. Without these co-conspirators, especially CCR5, the virus can't break and enter its target cells.

However successful the three-drug regimen is proving clinically, virologists know it is living on borrowed time. Eventually, HIV-1 will catch up and develop resistance to the antiprotease and antiretroviral compounds. By then, the drug designers had better come up with something new.

One paradigm shift in their endeavors may emerge from the Achilles heel in the AIDS virus, namely, its coreceptors — in particular, a virus-disabling mutation in the CCR5 gene. This 32-base-pair deletion apparently accounts for the previously unexplained twofold-lower likelihood of adult high-risk HIV-1 individuals to infection and progression of the AIDS virus. (See BioWorld Today, Feb. 13, 1997, p. 1, and March 4, 1997, p. 1.)

But what about their children, who may or may not inherit that protective altered gene from one parent or both?

An answer to that question comes from 512 children born between 1983 and 1996 to HIV-1-infected French mothers. It's spelled out in today's issue of The Journal of the American Medical Association (JAMA), dated Jan. 28, 1998, titled: "CCR5 chemokine receptor variant in HIV-1 mother-to-child transmission and disease progression in children."

Of that 512-baby cohort, 276 were infected, and 49 inherited the mutated gene from one parent (that is, were heterozygous for the deletion allele). Only one child was homozygous, having acquired the mutated gene from both parents, which may be why he escaped infection.

Genetic Link May Impact Therapies

Molecular biologist Micheline Misrachi, the paper's lead author, observed, "This is the first study to determine the effects of the mutation in children born to HIV-seropositive mothers." Fifty-two medical centers participated in the multicenter, prospective project, coordinated by the French Pediatric HIV Cohort, in Paris.

Those 49 heterozygous children were equally divided between the infected and noninfected groups. At three years of age, only 9 percent of them had advanced symptoms of AIDS (opportunistic infections, cancers, encephalopathies, etc.), as compared with 28 percent of homozygous kids, who had inherited the non-mutated, non-protective gene from both parents.

At age eight, on the other hand, just under half of the heterozygous youngsters, 49 percent, had no advanced symptoms, but 89 percent of the homozygous group did.

Besides these stigmata of HIV-1 infection, progression of severe immune deficiency differed markedly between the two allelic groups.

From these results, the French researchers derive the overall conclusion that "heterozygosity for the CCR5 32-deletion does not protect children from infection by the maternal virus, but substantially reduces the progression of the disease in HIV-1-infected children."

Beyond these childhood effects, the study's findings shed light on adult reactions to the mutant HIV-1 coreceptor gene.

"The impact of genetic factors may be more important or more easily detected when HIV infection occurs perinatally," suggested Thomas O'Brien, of the National Cancer Institute, in an editorial accompanying the JAMA article. "Perhaps," he speculated, "this is because children have less variability in other factors that alter prognosis or because the timing of initial infection is more precisely known."

O'Brien pointed out that "clinical testing for CCR5 genotype and other genetic markers is not currently indicated, because there is no evidence for altering therapy on the basis of such information."

But he made the point that a patient's response to antiviral drugs may in part be genetic, or that other gene variants which alter the risk of HIV-associated opportunistic infections may come to light, thus impacting antiviral therapies and anti-infection prevention. *

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