Suddenly today, there is big news in the war againstAIDS, namely, the outlook for natural HIV suppressors.These long-suspected, but never-before-identified factorsare raising visions of prognostic AIDS tests, vaccines and_ some day _ therapeutic compounds.
They offer answers to the mystery of why some HIV-infected people never go on to get AIDS.
Release of the news came in an unprecedented earlyrelease by Science when editors and researchers learnedof a similar report which was scheduled to appear intoday's Nature.
* Nature carries a two-column item headlined "HIVsuppression by interleukin-16." Its principal authors arevirologist Reinhard Kurth and co-authors at the Paul-Ehrlich-Institut in Langen, Germany. Accompanying thisbrief research communication is a somewhat lengthiereditorial comment titled "An elusive soluble suppressor,"by Anthony Fauci, director of the National Institute ofAllergy and Infectious Diseases.
* Friday's Science will run a two-page news article,"Elusive HIV-suppressor factors found." Originally, thisreport was scheduled to appear in the Dec. 15, 1995Science, introducing a research report titled"Identification of RANTES, MIP-1a, and MIP-1a, as themajor HIV-suppressive factors produced by CD8+ cells."Its principal authors are Robert Gallo, co-discoverer ofthe HIV, and his suppressor-team leader, Paolo Lusso.
Virologist-immunologist Lusso, with the team he led inGallo's laboratory at the National Cancer Institute (NCI),identified and tested the three virus-suppressingchemokines during the past year. Gallo retired from theNCI a month ago to found and direct his new Institute ofHuman Virology, as part of the University of Maryland,in Baltimore.
Lusso returned to his native Italy as chief of the humanvirology unit at the San Raffaele Scientific Institute inMilan.
Their Science paper describes three identifiedchemokines _ molecules that chemically attract cells _secreted by T lymphocytes adorned on their surface byCD8 receptors.
Lusso defined them for BioWorld Today: "RANTESstands for released on activation normal T-cell expressedand secreted. MIP-1a, and MIP-1b are more descriptive.They mean macrophage inflammatory protein."
Acting together, Lusso reported, these three presumednatural viral inhibitors appear to help slow theprogression of HIV in early stages of infection, and inpeople who fail to progress to full-blown AIDS for longerthan a decade.
When a predatory AIDS virus gets into its victim'sbloodstream, it makes for T cells that carry CD4receptors. These are HIV's keys to the kingdom ofinfection. One theory has it that the CD8 T cellscounteract this penetration by releasing thosechemokines, which cut the virions off at the CD4 pass.
In in vitro experiments with HIV-infected human cells,RANTES and the two MIPs inhibited assorted strains ofHIV-1, HIV-2 and SIV. Clinching their case, theinvestigators applied neutralizing antibodies directed atthe three chemokines to their cell cultures, and abolishedall of the HIV suppressor activity.
Kurth, principal author of the Nature paper, has long beenstudying why African Green Monkeys, thoughchronically infected with SIV, never come down with thesimian equivalent of AIDS, to which Asian primates areprone. Kurth reports isolating nearly identical IL-16chemokines from humans and African Greens, both ofwhose T cells suppress HIV replication.
Fauci pointed out that the IL-16 genes in both speciesvary by only 16 of their 390 coding nucleotides.
"In essence," Fauci observed, "the new [Nature] studyopens up fresh avenues of research into pathogenesis,treatment and vaccine development." He added, anentboth reports, "There is no question that this is door-opening time."
Close, But Not Quite The Holy Grail
Gallo told Science, "There is no reason to believe thatthis is the Holy Grail." But Lusso told BioWorld Todaythat he and Gallo, in their on-going, now trans-Atlantic,collaboration, are at present conducting toxicologystudies of their chemokines.
As for actual therapy, Lusso said, "Obviously, in thedeeps of our hearts there is that hope. But we have tofollow the rules.
"Once the toxicology is evaluated," he observed, "wehave to go for efficacy studies in animals, followed, wehope, by Phase I and II trials in humans. Only after thiscan we go on to wide-range, in vivo studies in patients.So it is really a long way down the road."
Along the way, he foresees valid clinical uses for testingthe chemokines in patients, as a prognostic indicator ofdisease progression. "If this is proven," he said, "it takesanother obstacle out of a possible therapeuticdevelopment."
He also sees the HIV suppression factors as "an excellentmarker of vaccine efficacy."
But eventual direct therapeutic application will need a lotmore work, Lusso cautioned: "Even though thesechemokines are natural, physiological factors, they mayprove to be highly toxic. Because the immune system iswisely releasing them at the right time, in the right place,in the right concentrations. And then they are gone."
He made the point that "these cell-attractant chemokinesare a focus of inflammation. If you give them in asystemic form, and they concentrate in some organs, theinflammatory response may be very dangerous."
At that point, Lusso would turn to biotechnology for help."The next step" he suggested, "could really bebiotechnological work, using genetic engineering _meaning modification, meaning peptides or other things_ to get rid of the unwanted effects."
He concluded: "If I had to make a prediction, I would saythat such modifications would one day lead to a suitablenew anti-AIDS drug, combined with many others in anoptimal cocktail." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.