In Sidney, Australia, 15 years ago, a sexually activehomosexual man in his early 20s donated blood at theRed Cross transfusion center. He was HIV-1-positive, butto this day, 15 years later, has not developed any of thesigns or symptoms of AIDS.
Neither have the seven transfusion recipients who sharedhis donor blood over the next three years, and so becameHIV-1-positive in turn. All but one (who died ofunrelated causes) remain healthy 10 to 14 years afterbecoming infected, and their CD4 lymphocyte counts _yardstick of HIV infection _ stay perfectly normal. Dittothe original donor, whom the Red Cross _ in aretrospective survey of contaminated-blood victims _traced, and code-named "D36".
Usually HIV-infected victims progress to full-blownAIDS within a decade at most, and succumb to lethalopportunistic diseases, such as Kaposi's sarcoma orpneumocystis pneumonia. Not so this "Sidney blood bankcohort" of seven unrelated non-progressors.
What makes their virus act so wimpy is a mutation thatdeletes its nef gene. This DNA sequence encodes the Nefprotein, which, said Australian molecular biologistNicholas Deacon, "is very important in the diseaseprocess." It apparently honchos high-level viralreplication in its target cells. "Ironically," Deaconobserved, "Nef was originally named to stand for`negative effector protein,' that is, having a negativeeffect on replication. Now we know that it's quite theopposite."
Deacon runs the AIDS molecular biology unit at theAustralian National Center for HIV Virology Research, inFairfield, Victoria. He is first author of a paper in today'sScience, "Genomic structure of an attenuated quasispecies of HIV-1 from a blood transfusion donor andrecipients."
"We have been able to get a sequence on regions of anumber of isolates of the virus from a number of thecohort members," Deacon told BioWorld Today, "andfully sequenced one viral genome." He and his co-authors"need to fully sequence more," he explained, "to be reallysure, and to obtain the infectious molecular clones as thebasis for a potential live attenuated vaccine." Suchprotective immunization, Deacon observed, "is perhapspointing to the best hope yet of the direction forproduction of a preventive vaccine."
Those seven Australians are not the first, but the second,reported examples of AIDS-free, HIV-1-infection by anef-deficient viral strain. Early this year, HarvardUniversity microbiologist Ronald Desrosiers reported thecase of a 44-year-old hemophiliac man, who received atransfusion of HIV-1-contaminated donor bloodsometime before 1983. (See BioWorld Today, Jan. 26,1995, p. 1.)
Like the seven Sidney subjects, he has suffered nosymptoms of AIDS or its hitch-hiking diseases; his CD4count stays at a healthy steady level, 12 years since heacquired the infection.
A Beautiful Experiment Of Nature
Desrosiers studies the nef gene and protein in monkeysinfected with simian immunodeficiency virus. He has along-term collaboration with vaccinologist DennisPanicali, president of Therion Biologics Corp.,Cambridge, Mass.
Panicali considers the seven Australian cases"remarkable." He told BioWorld Today, "It's just abeautiful natural experiment that these nef-deleted,attenuated viruses are, for at least ten to 14 years now,non-pathogenic. As these patients age, and they continueto remain healthy, that should give some sense that thesenef-negative HIVs may be non-pathogenic in the longterm as well."
As for a nef-deletion-based vaccine such as Deaconsuggested, Panicali voiced caveats at several levels: "Themajor concern that people have about live-attenuatedversions of HIV is that the viruses will persist for life,and we don't know what the long-term consequences ofthat are.
"Then," he continued, "there are questions about herdimmunity, or herd transmission. Because if they arepersistent, will they be transmitted sexually or throughblood transfusion to people who are at low risk, forinstance?
"And of course there will always be long-term questionsof efficacy. What these non-progressing patients haveshown so far is that they are not developing disease withthese viruses. But there's no concrete proof that they areprotected against infection with wild-type virus."
But Panicali wants to be sure that Therion will beprepared. "When _ if ever _ it may be possible, if theregulatory agencies, and the world itself, are willing, totest this type of vaccine, we would like to be in a positionthat Therion could provide it." This in ongoingcollaboration with Desrosiers and Harvard, from whichhis company licenses the technology.
Nef: Not Just Vaccine But Antiviral Drug
Should that day dawn, Panicali suggested, "Initially onewould provide the vaccine to the high-risk population,much as how the hepatitis vaccine entered the market.Gradually, as the safety and efficacy record grew over theyears, perhaps it could be expanded to the generalpopulation."
Deacon expressed his hope "that the publication of thispaper in Science will stimulate or rekindle publicdiscussion _ full, frank and robust discussion, as theysay _ on the use of a vaccine."
Besides that outlook, he also aims at targeting the nefgene and its protein product for an antiviral drug "thatinhibits the activity, or activities, plural, of the protein.The big stumbling block there, of course," he added, "ishaving a biochemical assay that you can use in screeningdrugs."
Not to worry. Right next door to his laboratory, Deaconadded, "two co-authors of this paper, D.A. McPhee andA.L. Greenway, [both of the AIDS molecular biology unitat the Australian National Center for HIV VirologyResearch] already are working up some biochemicalassays of Nef activity." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.