Discovery of protein chain may lead to new drugs and treatments
Researchers at the Johns Hopkins Bloomberg School of Public Health have identified a complex series of proteins that enable HIV to bypass the natural defenses of human cells and replicate. The discovery of these proteins is the key for understanding how HIV overcomes host defenses and could potentially be new targets for HIV medications. A study detailing the finding is published in the October 16, 2003, online version of the journal Science.
As the researchers explained in their article, viruses like HIV contain a viral infectivity factor (Vif), which is essential for evading the human cell's natural antiviral agent called APOBEC3G. To disable the antiviral agent, Vif interacts with a series of proteins to modify (polyubiquitination) and degrade APOBEC3G. Xiao-Fang Yu, MD, DSc, an associate professor with the School's Department of Molecular Microbiology and Immunology, and his colleagues have identified these proteins as Cullin5, Elongins B and C and Rbx1.
Together, they form a complex of proteins called ubiquitin E3 ligase (Cul5-SCF), which interacts with Vif and APOBEC3G.
"We've discovered a new link in the chain that allows the HIV to overcome the cellular resistant factor and to infect human cells," said Dr. Yu. "By identifying the proteins involved in this process, we may be able to develop new drugs and therapies for preventing HIV infection."
Through a series of laboratory experiments, Dr. Yu's team further found that disruption of the Cul5-SCF function makes HIV less infectious and less able of suppress APOBEC3G and its protective properties. HIV infectiousness was reduced 90 percent when Cul5 mutants were over expressed in combination with APOBEC3G.
Dr. Yu and his collaborators, Drs. Xianghui Yu, Yunkai Yu, Bindong Liu and Kun Luo, are working on further explaining the mechanism of Vif and Cul5 complex interaction and identifying strategies to block Vif function and consequently HIV infection.
"Induction of Ubiquitination and Degradation of APOBEC3G by HIV-1 Vif-Cul5-SCF" was written by Xianghui Yu, Yunkai Yu, Bindong Liu, Kun Luo, Wei Kong, Panyong Mao and Xiao-Fang Yu.
The study was funded by grants from National Center for Research Resources. Reagents were supplied by the AIDS Research Reagent Program, division of AIDS, NIAID, NIH.