About the middle of this month, the first of a dozen healthy, identicaltwins will begin donating blood to treat their matching siblings,infected with AIDS. This will not be the simple transfusion it soundslike, but an experimental anti-viral gene therapy.T lymphocytes in the donated blood, modified for their ability to killHIV-1-infected CD4 T cells, will be packaged with a retroviralvector carrying a gene designed to perform an end-run around theimmune system's key goal guard, MHC _ the majorhistocompatibility complex.That expression package, containing a recognition structure for HIV,will encode a chimeric protein. After several weeks of amplifying theCD8 cells ex vivo, it will be infused into the AIDS twin'sbloodstream. There, if all works as planned, the double-actingprotein will find and kill off that twin's HIV-infected T cells.Cell Genesys' senior vice-president/chief operating officer, DanielHoth, described the genetically engineered anti-HIV T cells as "anew potential AIDS therapeutic strategy that is directed against HIV-infected cells rather than at the virus itself, which is the target of allantiviral drugs currently used to treat AIDS."The National Institute of Allergy and Infectious DIseases (NIAID),in Bethesda, Md., NIH's principal anti-AIDS agency, will conductthe Phase I trial, for which twins began enrolling in the middle ofOctober. The dose-and-toxicity study, designed to take a year, is co-sponsored by Cell Genesys, Inc., of Foster City, Calif., under aCooperative Research and Development Agreement with NIH.By the end of 1995, the trial's NIAID director, Robert Walker,expects to have acquired enough Phase I dosage and toxicity data toembark on the second _ antiviral efficacy _ phase of the study,lasting until the end of 1996.In addition to the initial cohort, that Phase II trial plans to enlistanother 30 or so twin pairs for its fixed-dose regimen. They comefrom a series of about 150 mixed healthy/infected twin pairs, whichNIAID's Walker is following.The novel gene-therapy strategy was designed by Cell Genesys'director of cell biology and immunology, Margo Roberts, jointlywith viral immunologist Randal Byrn at New England DeaconessHospital, a teaching affiliate of Harvard Medical School.Journal Reports Proof-of-Concept In VitroDuring the clinical procedure, blood will be drawn, modified,cultured and infused every eight weeks. "Ultimately," Roberts toldBioWorld Today, "we intend to get this frequency to the point of notexactly instantly, but several days instead of weeks."Roberts is first author, and Byrn a co-author, of a paper in the journalBlood, out today. Its title: "Targeting of Human ImmunodeficiencyVirus-Infected Cells by CD8+ T Lymphocytes Armed WithUniversal T-Cell Receptors."It's those universal receptors that bypass the blocking MHCrestriction antigens. These are nature's way of making sure that whena T cell rushes to repel an invader, it "sees" not just the enemyantigen, but also the body's private "self" recognition factor that fitsthat antigen. By evading this restriction, the universal receptorspermit treating second parties with the enormously amplifiedpopulation of CD8 T cells."Killer T cells normally do not function when transplanted from oneindividual to another," Roberts explained, "because they must beable to simultaneously recognize an individual's specificimmunological fingerprint (MHC) in conjunction with the antigen onthe infected cell."By coincidence, just a week ago, the U.S. Patent and TrademarkOffice issued patent No. 5,359,046 covering "Chimeric Chains forReceptor-Associated Signal Transduction Pathways," with Robertsas a co-inventor.Byrn heads a laboratory in the hematology/oncology division atDeaconess. Once Cell Genesys had genetically engineered thechimeric T cells and high-efficiency retroviral transduction system,he told BioWorld Today, "Our role at Deaconess was functionalcharacterization of T cells containing their universal receptor. Wetested these cells for their ability to kill HIV-infected cells in vitro."In that expression system, Byrn explained, "two components arelinked. One of them, CD4+ T cells, recognize HIV's gp120 envelopeglycoprotein, the target antigen. The other activates the killer T cell'ssignaling function. The ultimate strategy," Byrn added, "was startingwith a multi-chain human monoclonal antibody gene, thengenerating a single-chain antibody from it, and using that as anantigen-recognition structure, linked to the signaling gene."The MHC restriction comes in, Byrn continued, when the normal Tcell receptor recognizes a fragment of an infected-cell antigenpresented to it by that target cell's MHC antigen. The T cell receptoris specific for both antigenic targets."In our case," he explained, "we have artificial target-recognitionstructures that recognize the intact target antigen, and no presentationby a particular MHC type is required. Ideally you'd like to be able tocreate one type of universal receptor that could be applied to anytype of patient with any MHC type."While the enriched and armed CD8 cells from the healthy twins arebusy lysing HIV-infected CD4 T cells in their infected siblings, theAIDS virus of course is busy infecting new target cells. "There is acontinuous fight between the rate at which the virus can infect newcells," Roberts observed, "and the ability of the immune system toinhibit the virus from replicating. We hope that by infusing theprocessed cells, we will reduce that viral activity."She added, "It doesn't even have to be 100 percent inhibition, but ifwe can just keep the virus at bay, that would make a significantimpact on the progression of the disease."Like Surgically Debulking A TumorByrn said that this goal of trying to kill as many infected cells aspossible, to curtail the continuous cycle of reinfection, isconceptually comparable to debulking a tumor to clear the way forother forms of cancer therapy. "Once you reduce the burden ofinfected T cells," he observed, "other drugs can kick in."But he noted one limitation of the experimental new approach: "Thecells that we're going to kill have to express the target antigen ontheir surface. A cell that is latently infected, that contains proviruswithin it, would not be susceptible to lysis."Another element of uncertainty is the never-ending mutation of HIV-1. "Basically, we don't know how effective our T cells are going tobe in response to new strains," Roberts said. "That is one of thethings we'll be actively looking at in the twin study." n

-- David N. Leff Science Editor

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