Researchers have confirmed for the first time the benefit of an innatedefense system present in the few patients who remain healthy afteryears of infection with HIV despite receiving no treatment, accordingto an article published in the September edition of the Journal ofVirology. The study found that the subset of HIV-infected patientsreferred to as long-term survivors or nonprogressors have higheramounts of a key enzyme in their white blood cells. At the same time, arelated biotech company is poised to begin preclinical testing on adrug designed to confer similar protection on most HIV patients.
Approximately five percent of patients with HIV, or humanimmunodeficiency virus, do not develop AIDS, or do so very slowly.Researchers have been trying for years to understand what setslong-term nonprogressors apart. Past research suggested that suchpatients maintain higher levels of an enzyme in white blood cellscalled APOBEC-3G (A3G), and the new study confirmed it in the firstexperiments on human cells.
Researchers at the University of Rochester Medical Centerbelieve that A3G "edits," or introduces changes in, the HIV geneticcode every time the virus copies itself. By doing so, A3G corrupts theHIV gene code and prevents the virus from reproducing. Unfortunately,HIV has evolved to counter A3G with viral infectivity factor (Vif), aprotein that "grabs" A3G and tricks the body into destroying it. Withthe "editing enzyme" gone, HIV is free to overwhelm the immune system,leaving patients vulnerable to AIDS infections that take three millionlives per year.
"Unlike nonprogressors, we believe that most people do notmake enough A3G to overcome the efforts by Vif to shut it down," saidHarold C. Smith, Ph.D., professor of Biochemistry and Biophysics at theUniversity of Rochester Medical Center, co-author of the J. Virologypaper and a founder of the biotech company, OyaGen Inc. "Our worksupports Michael Malim's seminal discovery while at the University ofPennsylvania, which suggested that protecting whatever amount of A3Gthat people do have from Vif represents a new way to attack HIV."
For two decades, medical center researchers have worked todetermine how families of editing enzymes, including A3G, make changesto DNA and RNA. The immune system recognizes the ability of editingenzymes to cause rapid genetic change and unleashes them on viral DNA.Researchers believe that the enzymes change the HIV genetic code soextensively that the virus loses the ability to code for its ownproteins and can no longer reproduce.
To confirm that A3G offers strong protection against HIV,researchers in the current study measured A3G levels in the immunecells of six people not infected with HIV and in 25 patients with thevirus. Of those with HIV, eight were long-term nonprogressors andseventeen had normal disease progression. None of those studied werereceiving antiretroviral therapy at the time blood was drawn.
In the study, the researchers found that higher levels of A3Gclosely corresponded to lower HIV viral levels. In addition, higherlevels of A3G were closely associated with higher CD4 T cell counts.Unless destroyed by HIV, helper T cells with CD-4 receptors targetbodily invaders for full-scale attack by the immune system.Furthermore, the team determined that nonprogressors have the most A3Gediting enzyme, followed by those not infected with HIV and lastly bythose progressing toward full-blown AIDS.
"Our study is immediately relevant to HIV research in severalimportant areas," said Xia Jin, M.D., Ph.D., assistant professor ofMedicine at the medical center and lead author of the J. Virologypaper. "In diagnostics, the work will establish a new prognostic markerfor AIDS by enabling the measurement of A3G levels in HIV-infectedpatients. It will also clarify a previously unrecognized mechanism thatunderlies slower disease progression in long-term nonprogressors.Lastly, the data suggest that protecting A3G from viral attack may bean important new way to treat AIDS and other viral infections," Jinsaid.A New Approach to HIV Treatment
Smith, with support from the University of Rochester TechnologySeed Fund, formed OyaGen in 2003. The biotech startup seeks to exploita family of 14 editing enzymes and related proteins as novel targetsfor the development of pharmaceuticals.
While OyaGen's platform technology has the potential toaddress several disease areas, the first focus is the treatment of HIV.The company's lead drug candidate interferes with ability of Vif todisable A3G. The experimental treatment is based on the work of HuiZhang, M.D., Ph.D., associate professor of Medicine at Thomas JeffersonUniversity (TJU) and on technology licensed from TJU.
As a dimer, Vif is able to come together like the two arms in apair of pliers to "grab" A3G. Once attached to A3G, Vif flags it fordestruction as part of an otherwise healthy protein recycling process.OyaGen's drug, a Vif Dimerization Antagonist (VDA), prevents the twohalves of Vif from linking up and leaves A3G free to "catastrophicallymutate" the HIV genetic code. In early experiments, OyaGen'stherapeutic has been successful in reducing HIV infectivity.
OyaGen recently completed an initial $1.5 million fundraisinground with investors including the technology seed fund and privateindividuals. The resources will support research and pave the way forsafety, toxicology, bioavailability and mode of delivery studies tobegin in October. Based on early successes, the company now seeks toraise between $10 million and $30 million to fund pre-clinical trialsand to support negotiations with the U.S. Food and Drug Administrationon the submission of a new drug application planned for 2006.
In addition, OyaGen in July signed a licensing agreement withthe University of Rochester for rights to the technology developed bySmith. The agreement covers novel drug targets with the aim ofprotecting A3G from viral attack. It also establishes a laboratory inthe university's technology incubator space.
"We hope to develop the first drug that solves the problem ofviral resistance, where viral strains have changed so quickly that HIVis resistant to current treatments in 40 percent of new cases," Smithsaid. "Our theory is that if the virus attempts to outsmart our drug bychanging Vif, it will leave itself open to attack by A3G. If earlystudies go as planned, OyaGen may be able to offer a treatment that HIVcannot easily escape."
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