An essential component of the HIV-1 molecular machinery responsible for infecting cells, the third variable loop (V3), consists of functionally specialized layers, according to investigators at the University of California San Diego Antiviral Research Center.
The surface of the HIV-1 particle is studded with protein spikes that allow the virus to enter human cells, including the V3 protein spike. Protein components like V3 are problematic because they are so diverse; up to 35% of the amino acids can differ between strains of HIV-1. Exposed to human antibodies, V3 rapidly evolves to avoid the immune system. However, the V3 loop’s critical function as a docking mechanism for HIV-1 to infect cells must impose limits on these evolutionary contortions, report the scientists.
The investigators developed a method that combines techniques from molecular evolution and artificial intelligence to investigate this loop. They reconstructed the evolutionary history underlying 1,145 genetic sequences encoding the V3 loop to discover groups of amino acids that were biologically dependent on each other. These coevolving amino acids formed ties across the V3 loop like rungs on a ladder, corroborating models from structural studies of the same protein.
The researchers caution that this study was restricted to a small portion of the genome. Nevertheless, the scientists report that the study identified important targets in the protein spike for future research. The paper is published in the November 23 issue of PLoS Computational Biology.