Fitness Landscape of Human Immunodeficiency Virus Type 1 Protease Quasispecies

Fernàndez, Guerau; Clotet, Bonaventura; Martı́nez, Miguel Ángel

doi:10.1128/jvi.01594-06

Cited by 52 publications

(50 citation statements)

References 64 publications

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“…In multi-peaked landscapes, evolutionary trajectories can become trapped on sub-optimal peaks, which may lead to (temporary) evolutionary stasis. While empirical information on the ruggedness of fitness landscapes remains scarce, significant progress has recently been made by systematically reconstructing neighboring genotypes that affect a specific molecular function, such as the resistance against an antibiotic (Burch and Chao 1999;Buckling et al 2003;Lunzer, Miller 2005;Bridgham, Carroll 2006;Miller et al 2006;Weinreich, Delaney 2006;Fernandez et al 2007), which has yielded some indications for the presence of multiple peaks (Korona, Nakatsu 1994;Poelwijk, Kiviet 2006;Poelwijk, Kiviet 2007;Salverda 2008). However, conclusively demonstrating that two adaptive peaks are distinct -and not interconnected by a ridge that circumvents the adaptive valley-remains difficult if not impossible, due to the high-dimensional nature of sequence space (Whitlock et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Poelwijk¹,

Tănase‐Nicola²,

Kiviet³

et al. 2011

Journal of Theoretical Biology

202

260

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Having multiple peaks within fitness landscapes critically affects the course of evolution, but whether their presence imposes specific requirements at the level of genetic interactions remains unestablished. Here we show that to exhibit multiple fitness peaks, a biological system must contain reciprocal sign epistatic interactions, which are defined as genetic changes that are separately unfavorable but jointly advantageous. Using Morse theory, we argue that it is impossible to formulate a sufficient condition for multiple peaks in terms of local genetic interactions. These finding indicate that systems incapable of reciprocal sign epistasis will always possess a single fitness peak. However, reciprocal sign epistasis should be pervasive in nature as it is a logical consequence of specificity in molecular interactions. The results thus predict that specific molecular interactions may yield multiple fitness peaks, which can be tested experimentally. 2 1. Introduction.

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Section: Discussionmentioning

confidence: 99%

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Poelwijk¹,

Tănase‐Nicola²,

Kiviet³

et al. 2011

Journal of Theoretical Biology

202

260

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“…51 HIV-1 and HCV share some characteristics, being both RNA viruses and producing persistent infections in humans. Consequently, we have found some common traits between these proteases.…”

Section: Discussionmentioning

confidence: 99%

Genetic and catalytic efficiency structure of an HCV protease quasispecies†

Franco¹,

Parera²,

Aparicio³

et al. 2007

Hepatology

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The HCV nonstructural protein (NS)3/4A serine protease is not only involved in viral polyprotein processing but also efficiently blocks the retinoic-acid-inducible gen I and Toll-like receptor 3 signaling pathways and contributes to virus persistence by enabling HCV to escape the interferon antiviral response. Therefore, the NS3/4A protease has emerged as an ideal target for the control of the disease and the development of new anti-HCV agents. Here, we analyzed, at a high resolution (approximately 100 individual clones), the HCV NS3 protease gene quasispecies from three infected individuals. Nucleotide heterogeneity of 49%, 84%, and 91% were identified, respectively, which created a dense net that linked different parts of the viral population. Minority variants having mutations involved in the acquisition of resistance to current NS3/4A protease inhibitors (PIs) were also found. A vast diversity of different catalytic efficiencies could be distinguished. Importantly, 67% of the analyzed enzymes displayed a detectable protease activity. Moreover, 35% of the minority individual variants showed similar or better catalytic efficiency than the master (most abundant) enzyme. Nevertheless, and in contrast to minority variants, master enzymes always displayed a high catalytic efficiency when different viral polyprotein cleavage sites were tested. Finally, genetic and catalytic efficiency differences were observed when the 3 quasispecies were compared, suggesting that different selective forces were acting in different infected individuals. Conclusion: The rugged HCV protease quasispecies landscape should be able to react to environmental changes that may threaten its survival. (HEPATOLOGY 2007;45:899-910.)

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“…There is a common consensus that the accumulation of amino acid mutations generates a genetic diversity and that the diversity is observed as a difference in protein function in phenotype. 5,6) In general, the mutation rate of viral proteins is much higher than that of protein in eukaryotes. Variants of a virus sometimes cause acute respiratory infection in humans and occasionally progress to a severe pandemic as seen in the recent emergence of highly pathogenic influenza viruses.…”

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confidence: 99%

“…9) Human immunodeficiency virus type 1 (HIV-1) protease is one of the most extensively studied viral proteins because of its importance as a target of antiviral drugs. 4,5) Since inhibition of the enzymatic activity hinders maturation of the viral precursor and leads to incomplete replication of the virus, inhibitors of HIV-1 protease are effective in chemotherapy for HIV-1 infectious diseases. HIV-1 protease is coded in the pol region of the viral genome and is expressed in a form of the pol precursor peptide.…”

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confidence: 99%

A Cluster Analysis on the Structural Diversity of Protein Crystals, Exemplified by Human Immunodeficiency Virus Type 1 Protease

Fudo

Neya

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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Information on many protein crystal structures has recently become available due to developments in crystallographic techniques. Even for a single kind of protein, several and sometimes many crystal structures are available. Human immunodeficiency virus type 1 (HIV-1) protease is one of the most extensively studied viral proteins, and about six hundred crystal structures have been determined. In this work, we examined the structural diversity of HIV-1 protease, classifying crystal structures into several groups from the viewpoint of similarity in atom geometry. Using 499 crystal structures downloaded from the Protein Data Bank (PDB), cluster analysis was applied to the whole body of HIV-1 protease and also to a limited number of residues at the binding pocket. As a consequence of clustering with regard to the whole body, 499 crystal structures were separated into 6 groups. It was found that a major factor for this separation is the space group of the crystals and that the space group strongly depends on the agents used in the protein crystallization. Amino acid mutation is a minor factor for separation in clustering. In cluster analysis for a limited number of residues at the binding pocket, crystal structures were not distinctly separated, and no clear factor linked to the separation was clarified. The results suggest that amino acid mutations have little effect on the coordinates of the main-chain atoms of HIV-1 protease. Hence, the changes in drug efficacy or substrate fitness caused by mutations are mainly due to the physicochemical features of amino acid side chains.Key words clustering analysis; crystal structure; amino acid mutation; drug resistance; space group Due to the progress in techniques for protein crystallization and in software for model building, crystal structures of many proteins have been elucidated. The reliability of solved protein structures has also increased.1) The development of a high-energy X-ray source has also been important for advancing crystallographic studies.2) Due to the progress in crystallographic technology, the availability of crystal structures in good quality has enabled us to examine structural differences in proteins in detail. Even for a single kind of protein, an amino acid mutation will cause the difference in its activity. Mutagenesis is one of the best approaches for clarifying the relationship between the protein activity and the mutated amino acid residue. Since protein activity has a close relation with its structure, 3,4) it is of great interest in molecular biology that the influence of amino acid mutation induces the change in protein structure.Apart from artificial mutagenesis, amino acid mutation ceaselessly occurs in the process of evolution. There is a common consensus that the accumulation of amino acid mutations generates a genetic diversity and that the diversity is observed as a difference in protein function in phenotype. 5,6) In general, the mutation rate of viral proteins is much higher than that of protein in eukaryotes. Variants of a virus som...

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Fitness Landscape of Human Immunodeficiency Virus Type 1 Protease Quasispecies

Cited by 52 publications

References 64 publications

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Genetic and catalytic efficiency structure of an HCV protease quasispecies†

A Cluster Analysis on the Structural Diversity of Protein Crystals, Exemplified by Human Immunodeficiency Virus Type 1 Protease

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