BLOOD CELLS THAT REMOVE HIVResearchers for Sheffield Medical Technologies Inc. of Houstonhave completed laboratory studies of a system to use modifiedred blood cells to remove HIV from circulation.
In the studies, red blood cells have the HIV-binding receptorCD4 electrically inserted onto their surface, where free AIDSvirus particles can attach, then be broken down when the redblood cell ends its normal life span of about 120 days and isengulfed and dismantled by macrophages.
The company (NASDAQ:SHEFU) supported studies by ClaudeNicolau at The Center for Blood Research Laboratories Inc., awholly owned subsidiary of The Center for Blood Research Inc.,an affiliate of Harvard Medical School and St. Lukes RooseveltHospital in New York . The studies showed that HIV from AIDSpatients was not transmitted to new white blood cells inperipheral blood containing CD4 attached to red blood cells, andthe virus did not infect macrophages.
The company's Phase I trial, begun in January 1992 at theVeteran's Affairs Medical Center in Houston, showed a"significant fraction" of the full-length CD4 protein remains onthe red blood cell for its entire life span, the companyannounced.
The company intends to choose a location this spring for aPhase II trial using stepped dosages of the red blood cell-CD4complex in 24 to 36 patients.
Sheffield funds research to obtain licensing rights andmanufacturing and marketing agreements with establishedcompanies. It holds an exclusive worldwide sublicense for redblood cell-CD4 electroinsertion technology, and holds optionsfor an ovarian cancer diagnostic, as well as for technology totreat prostate cancer and benign prostate hyperplasia.
SBIR TO STUDY HOW HIV ENTERS IMMUNE CELLS
Progenics Pharmaceuticals Inc. plans to study how HIV entersimmune cells under a new small business innovation research(SBIR) grant from the National Institutes of Health.
The private Tarrytown, N.Y., company will use the $50,000grant to develop a model of viral entry into CD+ T cells. HIVentry is mediated by attachment and fusion to these immunecells.
HIV-infected cells can also attach and fuse with uninfectedCD4+ cells, forming multinucleated giant cells known assyncytia. The appearance of syncytia is strongly associatedwith the development of AIDS-related complex (ARC) andAIDS.
Progenics' model system should assist understanding of HIVdisease, said Stephen Goff, professor of biochemistry andmicrobiology at Columbia University and chairman ofProgenics' scientific advisory board.
Progenics received an SBIR grant in 1990 to study screening ofmolecules to prevent binding of HIV to T cells, and an SBIRgrant in 1992 to work on AIDS vaccine development. This thirdgrant "will lead to a more comprehensive understanding of theviral life cycle," said Paul Maddon, chairman and chiefexecutive officer. The company would like to speed efforts todesign ways to block HIV infection, he explained.
KEY PROTEIN IN HIV REGULATORY LOOP IDENTIFIED
Studies at the University of California and the GladstoneInstitute of Virology and Immunology have identified a keyprotein in a HIV regulatory loop not seen before inretroviruses.
The protein, I-Kappa-B, breaks down inside T cells activated inresponse to infection and releases its partner protein NF-Kappa-B. The partner enters the T cell nucleus, where it turnson infection-fighting genes. However, in cells containing HIV,this step also initiates production of new copies of the AIDSvirus.
Once in the nucleus, NF-Kappa-B also stimulates production ofits inhibitor I-Kappa-B, which resumes control in a naturalbalancing system "that ultimately could lead to less HIV geneexpression," said Warner Greene, director of the GladstoneInstitute of Virology and Immunology at San Francisco GeneralHospital.
The inhibitor protein normally plays a role in cell growth andresponse to infection. The regulatory loop "may be the cell'smechanism for making sure you don't leave this potenttranscription factor (NF-Kappa-B) turned on all the time,"Greene said. Potentially, researchers might design super-inhibitors to control HIV transcription in infected cells. Thisresearch was described in the March 26 issue of the journalScience.
DYE NEUTRALIZES HIV IN TEST TUBES
South Dakota State University chemist David Lewis has found adye that neutralizes HIV in test tubes by locking shut the viralmembrane.
"It's like turning a paper pinata into a concrete pinata," Lewissaid about the yellow dye, which travels to membranes thatsurround cells and "enveloped" viruses, including HIV, herpes,hepatitis B and rabies. Exposed to blue light, the dye linksmembrane proteins together. The dye is non-toxic to normalcells in culture at concentrations that stop HIV from releasingits genetic material, a prerequisite of replication. In addition,the HIV binding protein gp120 apparently changesconformation so it can no longer attach to CD4 receptors onimmune system T cells.
Unlike most photodynamic agents, the dye does not requireoxygen, which broadens its potential uses and avoids creationof oxygen-free radicals that can harm healthy cells.
Animal toxicity studies have just begun and human tests areprobably five years away, Lewis said. If an HIV treatment doesnot arise from this compound, it might still be useful for tissuewelding or producing vaccines, since surface antigens appear tobe unaffected by the membrane-protein changes.
Lewis is trying to add a "molecular chunk" to absorb red light,which penetrates tissue better than blue light. His team is alsoexploring "pre-activating" the compound with blue light, thendelivering it to the bloodstream like conventional medications.
BIOCHEM PHARMA BEGINS PHASE II/III TRIALS
BioChem Pharma Inc. of Laval, Quebec (NASDAQ:BCHXF) isbeginning Phase II/III trials of the reverse transcriptaseinhibitor 3TC in patients infected with HIV. The multicentersurrogate marker trials will compare 3TC alone and incombination with AZT to AZT alone and AZT in combinationwith ddC. Patients in both early and advanced stages ofinfection will be enrolled.
Glaxo is managing the development of 3TC in a collaborativeagreement that also covers commercialization of the drug.
GROWTH HORMONE TESTED IN HIV-INFECTED PATIENTS
Researchers at the University of California and San FranciscoGeneral Hospital are testing growth hormone in HIV-infectedpatients who have experienced significant weight loss.
An initial trial at SFGH suggested the genetically engineeredhormone may be superior to other weight-gain therapies, saidMorris Schamebelan, a UCSF professor of endocrinology andprincipal investigator of the study.
Growth hormone may stimulate production of lean body mass,which has been linked to AIDS survival, and help burn body fatfor fuel instead of lean tissue. The multicenter trial of 130patients nationwide is sponsored by Serono Laboratories, whichmakes recombinant growth hormone. Patients must be takingan approved anti-viral such as AZT or ddI, and will receiveeither growth hormone or placebo for three months, followedby growth hormone for an indefinite period of time.
(c) 1997 American Health Consultants. All rights reserved.