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Study offers new way to discover HIV vaccine targets
Date:3/21/2013

s derived from Gag are important structural elements of the virus. For example, a protein called p24 makes up the capsid that surrounds the virus's genetic material.

Each position in HIV proteins can be occupied by one of 20 possible amino acids. Sequence data from thousands of different HIV strains contain information on the likelihood of mutations at each position and each pair of positions, as well as for triplets and larger groups. The researchers then developed a computer model based on spin glass models, originally developed in physics, to translate this information into predictions for the prevalence of any mutant.

Using this model, the researchers can enter any possible sequence of Gag proteins and determine how prevalent it will be. That prevalence correlates with the fitness of a virus carrying that particular protein sequence, a relationship that the researchers demonstrated by using the model to predict the fitness of a few dozen Gag protein sequences, and verified by engineering those sequences into HIV viruses and testing their ability to replicate in cells grown in the lab. They also tested their predictions against human clinical data.

Visualizing fitness

The model also allows the researchers to visualize viral fitness using "fitness landscapes" topographical maps that show how fit the virus is for different possible amino-acid sequences for the Gag proteins. In these landscapes, each hill represents sequences that are very fit; valleys represent sequences that are not.

Ideally, vaccine-induced immune responses would target viral proteins in such a way that mutant strains that escape the immune response correspond to the fitness valleys. Thus, the virus would either be destroyed by the immune response or forced to mutate to strains that cannot replicate well and are less able to infect more cells.

This would mimic the immune response mounted by people known as "elite controllers," who are
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Contact: Kimberly Allen
allenkc@mit.edu
617-253-2702
Massachusetts Institute of Technology
Source:Eurekalert

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