In many diseases, a mutated gene usually spells bad news. But a 32-base-pair deletion in a certain immune-system receptor heralds gladtidings to individuals infected with HIV.
Today's issue of Science reports the long-sought discovery in anarticle titled: "Genetic restriction of HIV-1 infection and progressionto AIDS by a deletion allele of the CKR5 structural gene."
Its findings go a long way toward explaining why some individualsinfected with the AIDS virus, even repeatedly, shrug off all clinicalsymptoms, while others take longer to contract the disease, and livelonger with it.
This story first broke at the molecular level toward the end of lastyear, in an embargo disconnect between Science and Nature. (SeeBioWorld Today, Dec. 7, 1995, p. 1.)
Research now has reached the point where potential screening forsusceptibility to HIV infection and AIDS disease has an apparentgenetic basis. So do potential preventive and therapeutic strategies.
It's a tale of two chemokine co-receptors, fusin and CKR5, whichtogether smuggle HIV virions into their cellular targets of infection.Fusin permits the viral envelope to fuse with the membranes of Tlymphocytes. (See BioWorld Today, May 13, 1996, p. 1.)
CKR5 (which stands for "cysteine-cysteine-linked chemokinereceptor) acts as fusin's co-conspirator. Its normal function is toattract macrophages to a site of inflammation.
An inherited mutation leaves that 32-base-pair gap in the gene's1,055 base-pair coding region, which expresses the CKR5 protein.It's this deletion that enables CKR5 to betray its fusin co-receptorpartner, thus blocking HIV from breaking and entering its target cell.
About 1 percent of Caucasians harbor this double inherited genedeletion, observes immunogeneticist Mary Carrington of the NationalCancer Institute (NCI), who is one of the Science paper's twoprincipal authors.
Double-Dose Mutation Confers HIV Immunity
"One of the two principal points in our article," she told BioWorldToday, "is that we found that individuals with a deletion on bothcopies are naturally resistant to HIV infection. That substantiatessimilar results obtained by others with smaller cohorts of testsubjects.
"The second thing," she continued, "is that for individuals whoinherit a deletion on only one copy of the CKR5 gene, the averagelength of time from HIV infection to AIDS disease is extended, onaverage from 10 to 13 years."
A person born with the mutant CKR5 gene variant inherited fromboth parents (homozygote) grows up HIV-proof, according to theresearch reported in today's Science. When only one parent passes onthe mutant allele, (heterozygote), viral infection occurs, but itsprogression to symptomatic AIDS is delayed. In those whose genomelacks the mutation entirely, HIV infection has free rein.
To reach these findings, Carrington and her co-authors at theNational Cancer Institute's Laboratory of Genetic Diversity analyzedthe DNA of 1,955 individuals whose HIV status was known, goingback many years.
The paper's senior author, geneticist Stephen O'Brien, observed:"Now that we are beginning to see the benefits of attacking HIV with,not one, but a combination of different drugs, today's finding pointsout a different, but naturally proven, angle from which to attack thevirus and make its life really rough."
The NCI team genetically mapped the fusin and CKR5 gene loci, theformer to the short arm of human chromosome 2; the latter tochromosome 3's short arm. They determined that mutant CKR5'sdeletion causes a frame shift at amino acid 185, which renders thereceptor non-functional.
The 1,955 HIV-1 high-risk individuals in whose DNA they thenlooked for the mutation came from six established AIDS cohorts:three of sexually active homosexual men, two of hemophiliacspreviously exposed to HIV-1 blood contamination; one ofintravenous drug users. Of the total 1,955, 1,343 were seropositive;812 seronegative.
Among those HIV-antibody-negatives they found 17 homozygotes _apparently protected from HIV infection by a double dose (maternaland paternal) of the CKR5 mutation.
In contrast, there was not a single homozygote among the 1,343virus-infected individuals. However, 195 of them were heterozygotic(gene variant from one parent only). The homosexual men who hadprogressed slowly to an AIDS diagnosis had more than twice as manyheterozygotic members as the rapid progressors, indicating partialprotection from the infection.
This phenomenon did not hold true for hemophiliacs, suggesting thatroute of transmission (blood transfusion versus mucosal epithelium)may be a factor.
Potential Prognosis, Diagnosis, Prevention, Treatment
"A lot of people out there," Carrington observed, "who are at highrisk but HIV-negative have very likely been exposed to the virus anumber of times. And they are not homozygous for the CKR5 genedeletion. We're looking at these individuals," she continued, "to seeif there are any other mutations, and we have in fact found some."
Her team is "also looking at different populations _ Caucasian,African-American, Native American, European _ a real HIVanthropological study."
The Science paper foresees the prospect for alternative antiviraltherapies based on, among other approaches:
* altered forms of CKR's ligands to block or delay infection;
* fragments of the viral envelope competing for HIV-1 binding siteson CKR5 cells,
* and gene-targeting constructs or drugs that inactivate the co-receptor.
Summing up, Carrington observed: "I think a number of labs will belooking at gene therapy, to see what can be done to addressprotection against HIV, using the information we now have onCKR5." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.