Abstract
BackgroundThe HIV-1 genome is subject to pressures that target the virus resulting in escape and adaptation. On the other hand, there is a requirement for sequence conservation because of functional and structural constraints. Mapping the sites of selective pressure and conservation on the viral genome generates a reference for understanding the limits to viral escape, and can serve as a template for the discovery of sites of genetic conflict with known or unknown host proteins.ResultsTo build a thorough evolutionary, functional and structural map of the HIV-1 genome, complete subtype B sequences were obtained from the Los Alamos database. We mapped sites under positive selective pressure, amino acid conservation, protein and RNA structure, overlapping coding frames, CD8 T cell, CD4 T cell and antibody epitopes, and sites enriched in AG and AA dinucleotide motives. Globally, 33% of amino acid positions were found to be variable and 12% of the genome was under positive selection. Because interrelated constraining and diversifying forces shape the viral genome, we included the variables from both classes of pressure in a multivariate model to predict conservation or positive selection: structured RNA and α-helix domains independently predicted conservation while CD4 T cell and antibody epitopes were associated with positive selection.ConclusionsThe global map of the viral genome contains positive selected sites that are not in canonical CD8 T cell, CD4 T cell or antibody epitopes; thus, it identifies a class of residues that may be targeted by other host selective pressures. Overall, RNA structure represents the strongest determinant of HIV-1 conservation. These data can inform the combined analysis of host and viral genetic information.
Highlights
The HIV-1 genome is subject to pressures that target the virus resulting in escape and adaptation
We built a map of the genome that shows the association between conservation and structural constraints: protein and RNA structure, and presence of overlapping coding frames (Figure 1)
We found that 11% of residues in CD8 T cell epitopes, 13% of residues in CD4 T cell epitopes and 18% of residues in antibody epitopes were under positive selection
Summary
The HIV-1 genome is subject to pressures that target the virus resulting in escape and adaptation. The virus is capable of genomic recombination, and most of its proteins tolerate coding variation [3,4] Based on this genetic diversity, HIV-1 can be classified into several types, groups, and subtypes [5]. There are recognized pressures that target the virus resulting in escape and adaptation (pressure exerted by the immune system or by antiviral treatment and bottleneck events such as transmission) [8,9]. These opposing forces need to be considered for a correct understanding of evolution of the viral genome
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