January 25, 2011 — Scientists at the University of Virginia and The Scripps Research Institute have determined the structure of the protein package that delivers the genetic material of the human immunodeficiency virus, or HIV, to human cells.
The work is the culmination of studies carried out over the last decade looking at different portions of the cone-shaped container, or the capsid. The final piece of the puzzle, described in an article published in the Jan. 20 edition of the journal Nature, details the structure of the two ends of the cone.
"This paper is a milestone for research from our group," said the study's senior author, Dr. Mark Yeager, a Scripps Research professor and staff cardiologist and chair of the Molecular Physiology and Biological Physics Department at the U.Va. School of Medicine.
A detailed description of the complete HIV capsid will provide a road map for developing drugs that can disrupt its formation and thus prevent infection by HIV.
HIV binds to receptors on human cells and then delivers the capsid inside them. Once inside a cell, the capsid comes apart, releasing its precious cargo – the virus' genetic material.
HIV then sabotages the cell machinery to make many copies of its genes and proteins. As new viruses are made, the genetic material is packaged into spherical immature capsids that HIV uses to escape from the infected cell. But before these newly released viruses can infect other cells, the immature capsid undergoes a dramatic rearrangement to form the mature, cone-shaped shell.
If formation of the mature capsid is disrupted, the virus is no longer infectious. Thus, new drugs targeting capsid formation could provide valuable additions to the arsenal of existing drugs against HIV.
Working primarily with husband-and-wife team Owen Pornillos and Barbie Ganser-Pornillos, investigators in his lab, Yeager partitioned the HIV capsid into smaller components, then determined their respective structures.
The researchers now plan to further refine the model using sophisticated computer programs to determine the stability of the structure in different regions and to identify possible "weak" points they can target using newly designed drugs.
They will also begin studying the structure of the immature capsid to determine how this version of the capsid transitions to the mature form – a step in the virus lifecycle that has remained mysterious.
"We don't have the full story yet, but we have volume one," Yeager said.
Research for the paper, "Atomic Level Modeling of the HIV Capsid," was funded by the U.S. National Institutes of Health and the Center for the Structural Biology of Host Elements in Egress, Trafficking, and Assembly of HIV, which is based at the University of Utah and directed by Dr. Wesley Sundquist.