HIV May Use Spring-Loaded Mechanism to Infect Cells
Peter S. Kim, an HHMI investigator at the Whitehead Institute for Biomedical Research, believes that the coiled-coil structure of a protein may provide HIV with the spike it needs to infect cells.
Researchers have found that a twisted rope-like structure called the coiled coil enables the flu virus to infect cells, and may also be important in infection with retroviruses -- the class of viruses that includes the human immunodeficiency virus (HIV).
In a report in the December issue of Nature Structural Biology, a team led by Peter S. Kim, a Hughes investigator at the Whitehead Institute for Biomedical Research at MIT, shows that the part of the HIV coat protein that is crucial for the virus's ability to fuse with and infect host cells also assumes a coiled-coil structure.
"We don't know yet if the structural similarities mean that HIV also uses a spring-like mechanism to fuse with host cells, but if further studies confirm that this is the case, it will help us better understand the mechanism of HIV entry into cells and suggest new ways to disrupt this process," said Kim.
Viruses are small infectious particles that need a cell's machinery to reproduce. Many viruses begin the infection process by fusing their own membranes to a cell's membrane, and then spill their contents into the cell. The membrane-fusion step is unique to viruses and therefore provides a potential target for the design of new, more effective antiviral drugs. "The remaining steps in viral infection are carried out by our own cells; it is difficult to block these later steps without harming our own cellular processes," Kim said.
Researchers had known that the flu virus's membrane-fusion process depends on a protein, called hemagglutinin (HA), that protrudes out of the viral membrane. Scientists had also identified a region of HA that is essential for fusion and called it the fusion peptide. When the structure of HA was first determined by HHMI investigator Don Wiley and his colleagues at Harvard, it was found that the fusion peptide is not located at the top of the HA molecule where it can interact with the cell's membrane. Instead, it is buried deep inside HA, and must move to the surface for infection to occur.
Two years ago, researchers in Kim's laboratory proposed that a loop region of the native protein "springs" out to form a three-stranded coiled-coil in the fusion-active form of the protein. When the HA structure is sprung, it dramatically changes shape, and the fusion peptide is launched into the cell membrane.
Over the past year, scientists in Kim's laboratory have extended their studies of viral membrane fusion to retroviruses including Moloney murine leukemia virus, simian immunodeficiency virus and HIV. They have shown that retroviruses contain a region with striking structural similarities to flu HA. They are currently studying whether retrovirus infection also requires a spring-loaded mechanism for membrane fusion.
Researchers have known that HIV's fusion depends on gp41, a protein located in the outer coat of the virus. Unfortunately, the structure of this key protein has not been amenable to structural studies since the purified protein aggregates in water, rendering it useless for most structural studies.
Kim's team has circumvented this problem by removing those parts of the protein that cause aggregation while still retaining the biologically relevant parts. This has enabled the scientists to study the structure of gp41 and to discover that it posseses a structure very similar to the coiled coil structure found in HA.