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Evolutionary modeling of rate shifts reveals specificity determinants in HIV-1 subtypes.

Penn O, Stern A, Rubinstein ND, Dutheil J, Bacharach E, Galtier N, Pupko T - PLoS Comput. Biol. (2008)

Bottom Line: Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification.When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance.Finally, we discuss mechanisms of covariation of rate-shifting sites.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
A hallmark of the human immunodeficiency virus 1 (HIV-1) is its rapid rate of evolution within and among its various subtypes. Two complementary hypotheses are suggested to explain the sequence variability among HIV-1 subtypes. The first suggests that the functional constraints at each site remain the same across all subtypes, and the differences among subtypes are a direct reflection of random substitutions, which have occurred during the time elapsed since their divergence. The alternative hypothesis suggests that the functional constraints themselves have evolved, and thus sequence differences among subtypes in some sites reflect shifts in function. To determine the contribution of each of these two alternatives to HIV-1 subtype evolution, we have developed a novel Bayesian method for testing and detecting site-specific rate shifts. The RAte Shift EstimatoR (RASER) method determines whether or not site-specific functional shifts characterize the evolution of a protein and, if so, points to the specific sites and lineages in which these shifts have most likely occurred. Applying RASER to a dataset composed of large samples of HIV-1 sequences from different group M subtypes, we reveal rampant evolutionary shifts throughout the HIV-1 proteome. Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification. We report further evidence for the emergence of a new sub-subtype, characterized by abundant rate-shifting sites. When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance. Finally, we discuss mechanisms of covariation of rate-shifting sites.

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Related in: MedlinePlus

The rate-shifting pattern at site 414 of gp120, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is involved in CCR5 binding.
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pcbi-1000214-g004: The rate-shifting pattern at site 414 of gp120, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is involved in CCR5 binding.

Mentions: Intriguingly, several sites in gp120 that are involved in the co-receptor CCR5 binding were detected as rate-shifting (Table 2), pointing at possible adaptations of different subtypes to different alleles of CCR5. For instance, the CCR5 Δ32 mutation is known to confer reduced susceptibility to the virus in Europe and western Asia [45], and this might affect the pattern of selection pressure acting on these sites. One example of a rate-shifting site affecting CCR5 binding is at position 414 of gp120, which was shown to be involved in CCR5 binding [46]. This site displays several rate shifts across a few of the subtypes (Figure 4), with threonine prevalent at subtypes C, F, J, and G, arginine prevalent at variant IDU-A, and relatively high variability in the rest of the subtypes. Clearly, at this site differing selection constraints operate at each subtype. One may speculate that these subtypes infect patients where a certain allele of CCR5 is more common, and the virus has adapted the gp120 protein to obtain enhanced binding. Future research is required to determine whether rate-shifting positions at subtypes correlate with the populations they infect.


Evolutionary modeling of rate shifts reveals specificity determinants in HIV-1 subtypes.

Penn O, Stern A, Rubinstein ND, Dutheil J, Bacharach E, Galtier N, Pupko T - PLoS Comput. Biol. (2008)

The rate-shifting pattern at site 414 of gp120, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is involved in CCR5 binding.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2566816&req=5

pcbi-1000214-g004: The rate-shifting pattern at site 414 of gp120, displayed on the phylogenetic tree of all seven subtypes.Each leaf (HIV-1 sequence) is color-coded according to the amino-acid it encodes at this position. Each leaf is labeled by its accession number, subtype (A, B, C, D, F, G, or J), and the encoded residue. The different subtypes are marked at each subclade of the tree. This site is involved in CCR5 binding.
Mentions: Intriguingly, several sites in gp120 that are involved in the co-receptor CCR5 binding were detected as rate-shifting (Table 2), pointing at possible adaptations of different subtypes to different alleles of CCR5. For instance, the CCR5 Δ32 mutation is known to confer reduced susceptibility to the virus in Europe and western Asia [45], and this might affect the pattern of selection pressure acting on these sites. One example of a rate-shifting site affecting CCR5 binding is at position 414 of gp120, which was shown to be involved in CCR5 binding [46]. This site displays several rate shifts across a few of the subtypes (Figure 4), with threonine prevalent at subtypes C, F, J, and G, arginine prevalent at variant IDU-A, and relatively high variability in the rest of the subtypes. Clearly, at this site differing selection constraints operate at each subtype. One may speculate that these subtypes infect patients where a certain allele of CCR5 is more common, and the virus has adapted the gp120 protein to obtain enhanced binding. Future research is required to determine whether rate-shifting positions at subtypes correlate with the populations they infect.

Bottom Line: Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification.When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance.Finally, we discuss mechanisms of covariation of rate-shifting sites.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Research and Immunology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
A hallmark of the human immunodeficiency virus 1 (HIV-1) is its rapid rate of evolution within and among its various subtypes. Two complementary hypotheses are suggested to explain the sequence variability among HIV-1 subtypes. The first suggests that the functional constraints at each site remain the same across all subtypes, and the differences among subtypes are a direct reflection of random substitutions, which have occurred during the time elapsed since their divergence. The alternative hypothesis suggests that the functional constraints themselves have evolved, and thus sequence differences among subtypes in some sites reflect shifts in function. To determine the contribution of each of these two alternatives to HIV-1 subtype evolution, we have developed a novel Bayesian method for testing and detecting site-specific rate shifts. The RAte Shift EstimatoR (RASER) method determines whether or not site-specific functional shifts characterize the evolution of a protein and, if so, points to the specific sites and lineages in which these shifts have most likely occurred. Applying RASER to a dataset composed of large samples of HIV-1 sequences from different group M subtypes, we reveal rampant evolutionary shifts throughout the HIV-1 proteome. Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification. We report further evidence for the emergence of a new sub-subtype, characterized by abundant rate-shifting sites. When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance. Finally, we discuss mechanisms of covariation of rate-shifting sites.

Show MeSH
Related in: MedlinePlus