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Characterizing Constraints Acting On HIV-1 Viral Evolution
Jeongmin Woo, Simon C. Lovell and David L. Robertson
Michael Smith Building, Faculty of Life Science, University Of Manchester
Contact: [email protected]
Abstract
Results
To identify the origin of constraints acting on HIV viral evolution, we examined
the relationships between sequence diversity and constraints from protein
structure, function and frequency of immune response number in site-to-site
manner. This was achieved by analysing site-specific sequence variability of the
amino acid sequence from entropy analysis through time for HIV functional
proteins. The evolutionary significance of an individual site is indicated by the
change in entropy along the time course: increasing entropy indicated that the site
is evolving predominantly in a clock-like manner, low entropy values with no
increase indicates a high degree of constraint and high entropy values indicate
lack of constraint. Mapping these sites onto the three-dimensional protein
structure we find a significant difference between evolutionary rates in regions
buried in the core of the protein as compared with those exposed on the surface.
This indicates that HIV evolution is affected by structural constraints above all,
and partially from functional constraints, with immunological constraint being more
complex. Elucidation of the factors constraining sequence variation in HIV-1 can
inform in vaccine development, since it allows the reduction of the number of
sequences that need to be considered
Figure 1. Ggenetic diversity of HIV-1 group M gag sequences.
Introduction
Due to their high rate of mutation and turnover, HIV viruses are
regarded as one of the fastest evolving organisms. The rapid
evolution of HIV can be seen in phylogenetic trees including global
variants. These show high levels of diversification since the
entrance of the virus into the human population in the early 20th
century [1,2]. Together with this, an increase in the evolutionary
distance of the virus was observed in many phylogenetic studies in
various epidemics [3]. However, HIV evolution must still be
restricted by constraints from structure and function.
In this study, using sequence diversity of HIV-1 sampled in the
last two decades and comparing sequence variability and
constraints in site-to-site manner, we investigate the constraints
acting on HIV evolution.
Figure 2. Constraints acting on HIV-1 evolution
•
Materials and Methods
•
•
Maximum likelihood (ML) trees were inferred from gag and env
sequences (obtained from http://www.hiv.lanl.gov).
Sequence variability at individual amino acid sites was
estimated by calculating normalized Shannon entropy score.
•
Entropy scores for sites were visualised on the 3D structure of
p17 as a colours representing each of its specific entropy range
(the warmer the color, the higher the entropy range and vice
versa).
•
The rate of sequence variation per site was quantified by the
slope of entropy change against sampling dates.
Solvent accessibility of individual amino acid sites were
estimated from PSA values.
Genetic divergence of global
HIV-1 does not increase through
time since the size of the ML
trees do not show remarkable
differences (Fig. 1A)
•
Limited diversification from the
tree data is supported by box
plots of pair-wise distances for
each tree that show slow increase
until 1997/1998, followed by a
plateau (Fig. 1B).
•
Diversity at individual sites is
dependent on the location of sites
in the structure. Sites with higher
sequence variability (warmer
colors such as yellow, or orange)
remain variable at the different
time points, while sites with lower
sequence variability (dark blue)
remain conserved through time
(Fig. 1C).
Conclusions
•
Divergence of HIV-1 group M does not show much increase over
the last two decades.
•
The slow increase in evolutionary distances is likely the result of
structural constraints and partly by functional constraints rather
than immune responses.
•
Sequence variation on each sites will also be affected by coevolution.
•
Potentially we can predict meaningful HIV evolution, which has
the potential to aid in vaccine designing strategies
.
Pair-wise genetic distances between individual strains were
calculated.
•
•
Model plot representing
different trajectories of
sequence evolution (Fig.
2A).
•
Acknowledgments
•
The skew in histograms shows
that there are more sites with
increasing diversity, while
increase is very slow or
negligible in most of the sites
(Fig. 2A).
•
This research is supported by the University of Manchester ORS
scheme. Thanks also to the Apple Research & Technology scheme for
computer support.
Most of the sites, which are
placed in the left center of the
chart, represents constrained
sites with no major change in
sequence variability (Fig. 2C).
References
1. Korber B, et al. Br Med Bull 2001; 58: 19-42.
2. Rambaut A, et al. Nat. Rev. Genet. 2004; 5: 52-61.
3. Bello G, et al. AIDS 2006; 20: 763-768.
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