Mapping of positive selection sites in the HIV-1 genome in the context of RNA and protein structural constraints

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.

Limits and patterns of cytomegalovirus genomic diversity in humans

“…These values differ from those estimated for other species. The number of conserved sites in the human genome is ∼8% (48), and, in other viruses, the proportion is much higher, including 66% for HIV (49), 63% for influenza A virus (50), and 78% for rubella virus (51). These trends suggest that the number of invariant sites is inversely correlated with genome size.…”

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

“…The proportion of population-level sequence variation attributable, at least in part, to HLA (defined as the proportion of sites in a given protein harboring at least one HLA-associated polymorphism) differs markedly by protein and is independent of the protein's overall conservation. For example, whereas the majority of variable Nef codons are attributable, at least in part, to HLA class I-mediated pressures, this explains only a quarter of Vpu sequence variation, implying the existence of other host factors in driving evolution of this viral gene (40,52,112) (to provide context, nearly 40% of variable sites in the highly conserved p24…”

Quantifying Selection against Synonymous Mutations in HIV-1 env Evolution

“…One possible explanation for a reduced fixation of synonymous variants in C2-V5 is secondary structure in the viral RNA, the disruption of which is deleterious to the virus (12,13,33).…”

“…In fact, the HIV-1 genome is full of RNA structures (10) with no or unknown function. However, large-scale modification of secondary structures can result in substantial reduction of the replication capacity (11), and the propensity of forming RNA stems anticorrelate with the rate of evolution (12,13). These poorly characterized RNA structures are conserved to different degrees in HIV-1 and simian immunodeficiency virus (SIV): corresponding regions tend to be part of similar structural elements, but individual base pairings are very rarely conserved (14).…”