In May and June of last year, scientists discovered severalnew receptors on the surface of immune-system cells that arerequired -- along with the long-known CD4 receptor -- forHIV-1 to enter and infect those cells.
Now, little more thana year later, researchers at the University of PennsylvaniaMedical Center and the University of Texas Medical Branch atGalveston have identified a small molecule that blocks oneof these so-called coreceptors, preventing infection by anumber of the HIV strains that target T cells. These strainsof the virus are associated with progression from relativelyasymptomatic HIV infection to the disease AIDS.
The discovery suggests that novel combination therapiesthat inhibit the full set of coreceptors could well proveeffective in preventing or treating HIV infection and AIDS.The findings are reported in the October 20 Journal ofExperimental Medicine. Two additional papers announcingsimilar results appear in the same issue.
"The importance of these studies is that theyprovide proof of principle," says coauthor Robert W. Doms,MD, PhD, an assistant professor of pathology and laboratorymedicine at Penn in whose laboratory many of the experimentswere conducted. "They show that we can develop smallmolecules to inhibit these newly identified coreceptors thatHIV absolutely needs to get into cells, thus preventinginfection."
The inhibitory molecule investigated in the study is asmall peptide called ALX40-4C, the anti-HIV activity ofwhich was first noted last year by senior author William A.O'Brien, PhD, at Galveston. Lead author Benjamin J. Doranz,BA, a researcher in Doms' laboratory, performed experimentsindicating that ALX40-4C operated by blocking one of thecoreceptors, CXCR4, which is used by the strains of HIV thatinfect T cells in the later stages of disease progression,known as T-tropic viruses. Another coreceptor, CCR5, is usedby viral strains that show a predilection for macrophages inthe earliest stages of infection, referred to as M-tropicviruses. Over time, in an infected person, viruses evolvefrom using CCR5 to using CXCR4, from M-tropic to T-tropic.
In one set of experiments, seven of ten strains of HIVisolated from patients by O'Brien used the CXCR4 coreceptor,and three of these relied on CXCR4 sufficiently to beblocked by ALX40-4C.
"One or more small molecules like this might delay orprevent evolution of the virus from using CCR5 to usingCXCR4," Doms says, noting that it is the viral strains thatuse CXCR4 that correlate with dropping T-cell counts andprogression to AIDS. "We also hope to develop small-moleculeinhibitors of CCR5, the receptor used by viruses that startan infection. To be fully effective in countering HIV, wemight need a cocktail that included a small-moleculeinhibitor of CCR5 in conjunction with one against CXCR4."
In addition to Doranz and Doms, the third Penn-basedcoauthor is Matthew P. Sharron, BA. Other coauthors on thepaper include Kathie Grovit-Ferbasi, Si-Hua Mao, and MatthewB. Goetz at the West Los Angeles Veterans Affairs MedicalCenter and the University of California at Los AngelesSchool of Medicine. Eric S. Daar with the Cedars-SinaiMedical Center and the UCLA School of Medicine is also acoauthor. ALX40-4C is manufactured by Allelix Inc.,Mississauga, Ontario, Canada.
Grant funding for this work was provided by theNational Institutes of Health. Doranz was supported by apredoctoral fellowship from the Howard Hughes MedicalInstitute.
The University of Pennsylvania Medical Center'ssponsored research ranks fifth in the United States, basedon grant support from the National Institutes of Health, theprimary funder of biomedical research in the nation -- $149million in federal fiscal year 1996. In addition, for thesecond consecutive year, the institution posted the highestgrowth rate in its research activity -- 9.1 percent -- ofthe top ten U.S. academic medical centers during the sameperiod.
Materials provided by University of Pennsylvania Medical Center. Note: Content may be edited for style and length.
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