Serial evolutionary networks of within-patient HIV-1 sequences reveal patterns of evolution of X4 strains

Abstract

BackgroundThe HIV virus is known for its ability to exploit numerous genetic and evolutionary mechanisms to ensure its proliferation, among them, high replication, mutation and recombination rates. Sliding MinPD, a recently introduced computational method [1], was used to investigate the patterns of evolution of serially-sampled HIV-1 sequence data from eight patients with a special focus on the emergence of X4 strains. Unlike other phylogenetic methods, Sliding MinPD combines distance-based inference with a nonparametric bootstrap procedure and automated recombination detection to reconstruct the evolutionary history of longitudinal sequence data. We present serial evolutionary networks as a longitudinal representation of the mutational pathways of a viral population in a within-host environment. The longitudinal representation of the evolutionary networks was complemented with charts of clinical markers to facilitate correlation analysis between pertinent clinical information and the evolutionary relationships.ResultsAnalysis based on the predicted networks suggests the following:: significantly stronger recombination signals (p = 0.003) for the inferred ancestors of the X4 strains, recombination events between different lineages and recombination events between putative reservoir virus and those from a later population, an early star-like topology observed for four of the patients who died of AIDS. A significantly higher number of recombinants were predicted at sampling points that corresponded to peaks in the viral load levels (p = 0.0042).ConclusionOur results indicate that serial evolutionary networks of HIV sequences enable systematic statistical analysis of the implicit relations embedded in the topology of the structure and can greatly facilitate identification of patterns of evolution that can lead to specific hypotheses and new insights. The conclusions of applying our method to empirical HIV data support the conventional wisdom of the new generation HIV treatments, that in order to keep the virus in check, viral loads need to be suppressed to almost undetectable levels.

Emergence, dominance, and possible decline of CXCR4 chemokine receptor usage during the course of HIV infection

“…Similarly, phylogenies reconstructed using only the V3 sequences were the same as with the whole gene fragment for each individual (data not shown). This, coupled with no evidence for recombination in the V3 loops of any individual in the dataset [Buendia and Narasimhan, 2009], suggests that the emergence of CCR5‐using strains from the CXCR4‐using population is not a result of recombination between circulating R5 and X4 strains. Transient CXCR4‐using viral populations have previously been described that emerge to dominate for a period during the course of infection and are subsequently replaced by a dominant CCR5‐using viral population but in these instances the later R5 dominance was a re‐emergence of the predominant R5 population [Ida et al, 1997; McDonald et al, 1997; Kitchen et al, 2004].…”

The CD8+T Cell Noncytotoxic Antiviral Responses

“…The X4-tropic/SI viruses infect established T cell lines and are associated with a more rapid disease course ( 82 , 83 ). The latter viruses generally appear at a later stage in HIV infection ( 84 , 85 ).…”

Live phylogeny with polytomies: Finding the most compact parsimonious trees

“…The ability to identify known common ancestors using molecular data has been successfully demonstrated with the Ebolavirus and Marburgvirus genera [10]. Patterns of evolution of HIV within patients have been shown to detect emergence of specific strains [11], using serial evolution networks, which resemble trees with extant ancestor nodes. In the area of paleontology, ancestors of species may be known and well characterized, prompting the need for phylogenetic reconstruction methods that account for labeled internal nodes.…”