Hiv反转宿主细胞空胞形成机制的萌芽
WESTPORT, CT (Reuters Health) - To escape from a host cell, HIV usurps the cell's own biochemical pathway that normally forms multi-vesicular bodies and turns that process "inside-out," according to research conducted in Salt Lake City.
"We knew that HIV's Gag protein co-opts the host's basic cellular machinery to help bud from the cell," Dr. Kenton H. Zavitz, co-author of the study and researcher with Myriad Genetics, told Reuters Health. "So we began looking for cellular proteins that would bind to Gag using Myriad's automated high throughput yeast-2 hybrid technology."
As reported in the October 5th issue of Cell, the research team identified the Tsg101 protein, which is involved in the vacuolar protein-sorting pathway, as a good candidate. "We showed that mutations in Gag known to inhibit budding also prevented Gag binding to Tsg101," Dr. Zavitz continued.
After that, he said, they implemented a new technique using small interfering RNA (siRNA), in which short sequences of double-stranded RNA that correspond to proteins of interest are introduced into the cell, which resulted in complete deletion of that protein. After depleting Tsg101 from human cell lines, "it gave the exact same late domain phenotype in which the virus-like particles get hung up on the surface of the cell," the researcher said.
Tsg101 appears to be the entry point by which the virus co-opts the pathway normally used by the cell to sort proteins for recycling or degradation. These proteins are required for the formation of "multi-vesicular budding vesicles."
"Normally, you have these small vesicles budding from the cytoplasm into a late endosomal compartment," Dr. Zavitz said. "The topology of that budding is identical to the topology of how the virus buds out of the cytoplasm and out of the cell. So the virus is basically taking this normal cell process and turning it inside out."
Myriad hopes to develop small molecules capable of inhibiting this pathway and exerting anti-HIV activity. "In the next several years, the percentage of drug-resistant HIV mutants will rise dramatically," Dr. Zavitz predicted. "This very exciting pathway may help us identify a completely new class of antivirals and a new way to combat HIV and AIDS.", 百拇医药
"We knew that HIV's Gag protein co-opts the host's basic cellular machinery to help bud from the cell," Dr. Kenton H. Zavitz, co-author of the study and researcher with Myriad Genetics, told Reuters Health. "So we began looking for cellular proteins that would bind to Gag using Myriad's automated high throughput yeast-2 hybrid technology."
As reported in the October 5th issue of Cell, the research team identified the Tsg101 protein, which is involved in the vacuolar protein-sorting pathway, as a good candidate. "We showed that mutations in Gag known to inhibit budding also prevented Gag binding to Tsg101," Dr. Zavitz continued.
After that, he said, they implemented a new technique using small interfering RNA (siRNA), in which short sequences of double-stranded RNA that correspond to proteins of interest are introduced into the cell, which resulted in complete deletion of that protein. After depleting Tsg101 from human cell lines, "it gave the exact same late domain phenotype in which the virus-like particles get hung up on the surface of the cell," the researcher said.
Tsg101 appears to be the entry point by which the virus co-opts the pathway normally used by the cell to sort proteins for recycling or degradation. These proteins are required for the formation of "multi-vesicular budding vesicles."
"Normally, you have these small vesicles budding from the cytoplasm into a late endosomal compartment," Dr. Zavitz said. "The topology of that budding is identical to the topology of how the virus buds out of the cytoplasm and out of the cell. So the virus is basically taking this normal cell process and turning it inside out."
Myriad hopes to develop small molecules capable of inhibiting this pathway and exerting anti-HIV activity. "In the next several years, the percentage of drug-resistant HIV mutants will rise dramatically," Dr. Zavitz predicted. "This very exciting pathway may help us identify a completely new class of antivirals and a new way to combat HIV and AIDS.", 百拇医药