By David C. Holzman

WASHINGTON --Long-term survivors infected with HIV may be genetically different fromthose whose disease progresses more normally, and triple-drug therapy with nucleosideanalogs loses effectiveness because the virus quickly mutates and becomes resistant,researchers reported Friday.

The data were presented at a workshop sponsored by the Institute of Medicine titled“Toward an Understanding of the Correlated of Protective Immunity to HIVInfection.“

Long-term survivors were about twice as likely to have certain genes in HLA class 2alleles as those with full-blown AIDS, Susan Buchbinder of the AIDS Office at the SanFrancisco Department of Public Health reported.

The class 2 gene products are present on antigen-presenting cells involved inactivation of CD4 positive cells, said Buchbinder.

The big question, she said, is whether the long-term survivors are a distinct group orthe tail of a random distribution. She said her results suggested the former, and “Ihope this will lead to exploring mechanisms.“

But during a question session, David Baltimore of Rockefeller University argued thatBuchbinder's results offered no hint of a plateau in the graph of disease onset.

Buchbinder's study involved a cohort of 6,704 men who had visited a sexuallytransmitted disease clinic and who have been studied by the Centers for Disease Controland the San Francisco Department of Public Health since 1982.

Long-term survivors were defined as those who had maintained CD4 counts above 500 formore than a decade. Their CD4 counts declined much more slowly than those of people withAIDS --0..8 percent per year vs. 80.5 per year, on average.

Resistance to Therapies

Following Buchbinder, George Shaw of the University of Alabama, Birmingham, presentedevidence showing that HIV can very quickly develop resistance to therapies using severalconventional compounds concurrently.

Nineteen men received AZT and ddC, or AZT and ddl, plus nevarapine, together. In eachcase, CD4 counts rose dramatically (from around 106 to 170 in one man, for example) butthen quickly fell back to baseline. As CD4 count rose and fell, the virus population felland then rose, said Shaw. The occurrence of mutation correlated with bottoming out n thevirus populations and topping out of CD4 count.

The mutations were changes in amino acid positions 181 and 188 of the reverestranscriptase gene, which are known to confer drug resistance.

By the 18th week of drug therapy, all patient viral populations had become drugresistant, but in 10 of the patients, the change had taken place within a week.

Furthermore, “genetic resistance was detectable after a five-week drugholiday,“ said Shaw.

“So the genotype, the phenotype, and all the virologic markets allcorrelate,“ he concluded.