Site-Specific Evolutionary Rate Shifts in HIV-1 and SIV

Abstract

Site-specific evolutionary rate shifts are defined as protein sites, where the rate of substitution has changed dramatically across the phylogeny. With respect to a given clade, sites may either undergo a rate acceleration or a rate deceleration, reflecting a site that was conserved and became variable, or vice-versa, respectively. Sites displaying such a dramatic evolutionary change may point to a loss or gain of function at the protein site, reflecting adaptation, or they may indicate epistatic interactions among sites. Here, we analyzed full genomes of HIV and SIV-1 and identified 271 rate-shifting sites along the HIV-1/SIV phylogeny. The majority of rate shifts occurred at long branches, often corresponding to cross-species transmission branches. We noted that in most proteins, the number of rate accelerations and decelerations was equal, and we suggest that this reflects epistatic interactions among sites. However, several accessory proteins were enriched for either accelerations or decelerations, and we suggest that this may be a signature of adaptation to new hosts. Interestingly, the non-pandemic HIV-1 group O clade exhibited a substantially higher number of rate-shift events than the pandemic group M clade. We propose that this may be a reflection of the height of the species barrier between gorillas and humans versus chimpanzees and humans. Our results provide a genome-wide view of the constraints operating on proteins of HIV-1 and SIV.

Keywords: HIV; cross-species transmission; phylogenetics; rate shifts.

Figure 1

Projection of Env₄₅₈ on the HIV-1/SIV phylogeny. Each leaf (corresponding to an HIV/SIV strain) is color-coded based on the amino acid present at Env₄₅₈. The legend shows the three most prevalent amino acids found at this site. The substitution rate of Env₄₅₈, which interacts with the CD4 receptor, was found to be slower in HIV-1 group M than in the rest of the phylogeny, with the branch separating both clades marked by an arrow.

Figure 2

(A) Proposed rate deceleration (red) and acceleration (blue) events in prominent branches shown along the genome using the coordinates of the HXB2 reference strain. (B) Proposed rate-shift patterns in prominent branches, shown on the phylogeny. Rate shifts (deceleration left and acceleration right) are shown as the percentage of total rate-shift events at each branch, while controlling for protein size.

Figure 3

Projection of the identified rate decelerating sites for the prominent branches onto the structure of Vpu (left, PDB ID: 2N28) and Nef (right, obtained from [44]).