Researchers are beginning to map out the series of rapid and efficient events used by HIV to create more virus particles inside a single host cell. Once HIV has infected a cell, it uses the cell to make many more infectious virus particles that are then released to infect new cells.
The most recent HIV drug treatments target the virus particles that are released from cells. New therapies may target the virus before it can assemble other virus particles.
"By targeting virus assembly, you will have some infected cells, but the virus won't be infecting 1,000 more cells," explains Dr. Jaisri Lingappa, assistant professor of pathobiology and adjunct assistant professor in the Division of Allergy and Infectious Disease.
Lingappa studies the cellular mechanisms involved in the assembly of the HIV capsid. The capsid is the protein shell encapsulating the HIV virus. It is unlikely that the 2,000 proteins needed to form a single virus capsid come together on their own, according to Lingappa.
"The virus most likely needs 'machinery' to assemble the proteins in the virus shell," she says. "The virus doesn't have the necessary components, so it's likely that the virus hijacks the host cell's machinery."
Lingappa's team has mapped a pathway by which a virus uses energy from a host cell to make copies of itself.
"The fact that the virus takes energy from the cell is important evidence that there is a use of host proteins," says Lingappa.
Lingappa is currently researching HP68-a host protein that appears to be used during virus assembly. Understanding exactly how this protein functions inside a cell will offer insight into how HIV uses a cell for its own purposes.
Lingappa uses a classic cell-biology technique called the cell-free approach, using parts of cells instead of whole cells. This technique won Howard Hughes Medical Investigator Gunter Blobel, of The Rockefeller University, the 1999 Nobel Prize in Physiology or Medicine. Blobel, a cell biologist, pioneered the process to study the functioning of proteins inside a cell. Lingappa is applying the cell-free approach to the study of how the HIV virus proteins function inside a cell.
"The complicated environment inside a cell is basically a black box," says Lingappa. "Using cell extracts, we can better manipulate the environment. We can stop and start chemical processes to control what's going on. By depleting HP68 from our cell extracts, we've caused the virus capsids to stop being produced. Production resumes when HP68 is added back."
HP68 is a present in many cells and now Lingappa's team is beginning to understand its role in the propagation of the HIV virus.
"All of the things required by the virus are possible targets," says Lingappa. "We need to understand a lot more about how this protein works - how the virus makes it work and what it is doing in the cell."
Lingappa received a Ph.D. in cell biology in 1988 from Harvard University's Division of Medical Sciences and an M.D. from the University of Massachusetts Medical School, Worcester, in 1987. From 1987 to 1990 Lingappa completed an internship and residency in internal medicine at the University of California at San Francisco (UCSF). In 1990 she became a fellow in infectious disease and subsequently an assistant clinical professor in the Department of Medicine at UCSF. From 1991 to 1999 Lingappa was also an attending physician at the Department of Emergency Services at San Francisco General Hospital.
She joined the UW School of Public Health and Community Medicine's Department of Pathobiology in 1999. Working with her in the laboratory are pathobiology graduate students Patti Kiser and Julia Dooher, and UW undergraduate Tom Maulhardt.
Lingappa has received several NIH awards for her research on viral assembly and the HIV virus. In 2000 she received a New Investigator Award from the UW Center for AIDS Research.
