Like a thief in the night, the AIDS virus infects its victim allunbeknownst until years later, when it's too late. That's the popularpicture of how HIV, the human immunodeficiency virus, gets itsstealthy start. It's not entirely true.Some unfortunate individuals check into the hospital emergency roomwith nausea, vomiting, sore throat, cough, fever and swollen lymphnodes in the neck, soon after the virus invades.This acute clinical syndrome usually feels like a case of flu _ nothingreally to worry about. "But if you're in a group at high risk of AIDS,"warns immunologist Raflick Sekaly, "such symptoms should make youworry."Sekaly is a co-author of a paper appearing in the forthcoming issue ofNature, out next Thursday. Its title: "Major expansion of CD8+ T cellswith a predominant Vb usage during the primary immune response toHIV."The article's principal author is Anthony Fauci, director of the NationalInstitute of Allergy and Infectious Diseases (NIAID). He presented thefindings on Monday to a plenary session in Yokahama of the 10thInternational Conference on AIDS.Sekaly, who directs the immunology laboratory at the MontrealInstitute of Clinical Research, told BioWorld Today that these flu-likesymptoms represent "a very strong immune response" mounted againstthe HIV's initial onslaught."Only about 20 to 25 percent of HIV-infected individuals getsomething disturbing enough to take them to the emergency room,"Sekaly said. Another 30 to 40 percent suffer milder but perceptiblediscomfort. The acute misery usually lasts about four weeks, duringwhich the viral blood count goes down "dramatically."Which raises the question: Why, if in most cases the victim's immunedefenses react so promptly and robustly, does AIDS remain a long-term, inescapable death sentence?"That's the million-dollar question," Sekaly said. "It's my impressionthat this response is detrimental to the individual." He sees two possibleanswers:One: "Assuming that the virus mutates, as it does, it is very likely thatone of the antigenic sequences to which the immune response istargeted might also change."Two: "The response is so strong that it exhausts the immune system'sdefenses. We are now trying to discriminate between these twopossibilities."His lab and Fauci's are collaborating to trace this precocious andtransient immune response at the molecular and cellular levels,respectively. They work with frozen blood samples from half a dozenAIDS victims who took their symptoms to hospital emergency roomsin recent years, and who have been followed by infectious-diseaseclinicians and hematologists at the University of Alabama inBirmingham."If we understand the mechanism that governs this very strong immuneresponse," Sekaly explained, "then we might have a handle on why theinfection progresses, and how the immune system is destroyed."Sekaly's lab has generated new analytical reagents, derived frompolymerase chain reaction technology, to quantitate all of the variableregions of the T cell receptor expressed in an individual. He explained:The T cell receptor, very much like an antibody, is a highly diversemolecule. "T cells are a family of lymphocytes. Under the microscope,100,000 lymphocytes all look alike. Yet each has a different T cellreceptor, which enables each one to recognize a specific antigen."The T cell receptor has two highly variable chains, alpha and beta.Testing the blood of one of the six donors indicated that his Vb sub-receptor population, "which expanded so dramatically early in theinfection," was homing in on HIV's gp120 envelope protein."When the T cells themselves swung into action, those with CD4-positive receptor subsets act merely as "helpers." They help the body'sB cells make antibody; they help the cytotoxic T cells kill off HIV-infected cells.These killer cells, "the ones critically involved in defending youagainst the virus," Sekaly said, are armed with CD8-positive receptorsubsets.So far, the Nature paper states, "the biological and clinical significanceof this type of immune response is unknown." But it noted that the twopatients "who experienced the most dramatic Vb expansion, progressedto AIDS within 12 months" and died.It concludes: "This type of immune response may be typical of otherviral infections, and may be critical for antiviral immune surveillance."In Other News From The Conference:u Genelabs Technologies Inc., of Redwood City, Calif., will pursuePhase III clinical trials of its antiviral compound, GLQ223, for HIVafter results of Phase II studies showed the drug is an "active agent" inthe treatment of the disease.Genelabs' two-year Phase II trial involved 150 HIV-infected patientswho were randomly selected to receive AZT, GLQ223 or acombination of the two. The goal was to slow the decline of CD4+Tcells over six weeks or reduce clinical disease progression.u Wellcome plc, of London, said it has five new anti-HIV compoundsin development. Three are reverse-transcriptase inhibitors, which havethe same mode of action as the company's AZT drug, Retrovir.Another compound is a protease inhibitor and the fifth is aimmonomodulator.u Viagene Inc., of San Diego, said a Phase I clinical trial of its ex vivogene therapy product for treatment of HIV involved four asymptomaticHIV-infected patients participated. Results showed no adversetreatment related events and CD4 cell levels in all four patientsremained stable. The HIV-IT gene therapy is an ex vivo form ofViagene's HIV ImmunoTherapeutic product.u Medarex Inc., of Princeton, N.J., said that laboratory studies of itsBispecific antibody, MDX-240, showed the drug neutralizes infectionof CD4 positive immune cells by clinical isolates of HIV and can targeta broad variety of HIV strains. The company has begun enrollingpatients in a Phase I/II clinical trial of MDX-240. The drug is designedto activate the immune system through a target-trigger mechanism. Oneportion of MDX-240 binds to a protein associated with HIV and theother portion of the drug is a patented antibody that recruits immunesystem killer cells. n* Jay Levy, of the University of California at San Francisco's CancerResearch Institute, said baboons are a promising animal model forAIDS because they not only can be infected with HIV, but they alsodevelop AIDS.Levy said baboons have immune systems similar to humans and he isusing the animals to study how activated CD8+ cells prevent HIVinfection from progressing to full-blown AIDS. Levy added that whenAIDS develops only after CD8+ cells lose their anti-HIV activity.* The Community Programs for Clinical Research on AIDS, a branchof the National Institutes of Health, is conducting one of the largeststudies to date of oral ganciclovir for prevention of cytomegalovirusinfection (CMV), one of the most serious opportunistic diseasesacquired by HIV-infected patients.The study, which involves 995 CMV-infected volunteers at 16 sites inthe U.S., will be conducted through June 1995. Two-thirds of theparticipants will receive 12 capsules, or three grams, a day of oralganciclovir and the other third will receive a placebo.CMV normally causes a latent infection, but when AIDS is present, itcan cause blindness and gastrointestinal problems, such as diarrhea,wasting, severe pain and death.
-- David N. Leff Science Editor
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