In a paper published in today's Science magazine, Los Alamos theoretical biologist Bette Korber, physicist Tanmoy Bhattacharya and their colleagues detail how they used the Laboratory's supercomputers to analyze the extensive HIV-1 sequence data compiled at the Los Alamos AIDS and Human Retroviruses Database and estimate the timing of the origins of the strains of HIV that have resulted in the infection of 50 million people. The Database is supported by National Institutes of Health.
"It is important to establish the timing of early events in the AIDS epidemic so that we can begin to examine hypotheses concerning the events surrounding the introduction and spread of HIV in humans," Korber said. "It's also vital to understand the speed with which the virus accumulates mutations so that we can better understand what it will take to design successful vaccines."
HIV is considered to be the result of chimpanzee-to-human transmission since it is most closely related to a group of simian immunodeficiency viruses (SIVs) found in chimpanzees that have a geographic range in West Equatorial Africa. Current evidence suggests that the HIV-1 M group, the main group of viruses, is likely to have resulted from one of those transmission events. Previous efforts to date the most recent common ancestor of the M group have yielded less accurate results because they were based on fewer HIV-1 sequences and used less refined evolutionary models.
In the recent study, physicists Bhattachurya and James Theiler produced a computer code and provided a statistical analysis; the Laboratory's Nirvana supercomputer was used for generating the computationally intensive phylogenetic trees, and a maximum likelihood method was developed for correlating distances between branches in a genetic tree to the passage of time.
Using HIV sequences sampled between 1980 and 1989, Korber created phylogenetic trees to organize the sequences according to their genetic relatedness by using an evolutionary model that incorporates some of the peculiarities of HIV evolution. This tree was then used as a basis to extrapolate back to the most recent common ancestor.
The length of the branches in the immense tree represented the extent of genetic change between HIVs; more closely related viruses are associated and have shorter branches separating them, more distantly related viruses have long branches. The branching patterns were based on calculations performed with the supercomputer, beginning with a comprehensive set of HIV sequences with known dates of sampling.
The researchers then worked backward to estimate the most likely model to describe the evolution of the virus. The rate of evolution determined using this tree - as well as a biologically motivated model for considering error in both time and genetic distance - allowed the researchers to determine the time of the ancestral sequence to be within the first half of the 20th century.
The phylogenetic tree for HIV was calculated using maximum likelihood methods. These are considered among the best methods for answering statistical questions of this kind, but require large amounts of computational resources. Because the researchers used Nirvana, the fastest unclassified supercomputer in the world, they were able to process vast numbers of candidate phylogenies relatively quickly and with considerable accuracy, and to statistically analyze their evolutionary model.
To calculate the time of origin, the researchers used strategies that permitted them either to assume a constant rate of evolution or to factor in a changing rate. Agreement between the two calculations enhanced confidence in the results.
The researchers also tested their methodology by using it to estimate the timing of two historically documented points in the HIV family tree -- the sampling time of the oldest available HIV sequence (1959) and the origin of the epidemic in Thailand (near 1986). The Los Alamos method estimated these events accurately.
The research was funded through Los Alamos' Laboratory-Directed Research and Development program, the National Institutes of Health and the Pediatric AIDS Foundation.
Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, The Babcock & Wilcox Company, and the Washington Division of URS for the Department of Energy's National Nuclear Security Administration.
Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health, and global security concerns.