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Patterns of HIV-1 protein interaction identify perturbed host-cellular subsystems.

MacPherson JI, Dickerson JE, Pinney JW, Robertson DL - PLoS Comput. Biol. (2010)

Bottom Line: Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID.Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction.Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) exploits a diverse array of host cell functions in order to replicate. This is mediated through a network of virus-host interactions. A variety of recent studies have catalogued this information. In particular the HIV-1, Human Protein Interaction Database (HHPID) has provided a unique depth of protein interaction detail. However, as a map of HIV-1 infection, the HHPID is problematic, as it contains curation error and redundancy; in addition, it is based on a heterogeneous set of experimental methods. Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID. Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction. The functional cohesiveness of these protein sets was validated using a human protein-protein interaction network, gene ontology annotation and sequence similarity. Next, using a distance measure, we group host protein sets and identify 37 distinct higher-level subsystems. We further demonstrate the biological significance of these subsystems by cross-referencing with global siRNA screens that have been used to detect host factors necessary for HIV-1 replication, and investigate the seemingly small intersect between these data sets. Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection. Moreover, we characterise the patterns of interaction that contribute to these perturbations. Thus, our work disentangles the complex set of HIV-1-host protein interactions in the HHPID, reconciles these with siRNA screens and provides an accessible and interpretable map of infection.

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Related in: MedlinePlus

Tree showing the relationship between significant biclusters and higher-level host subsystem groupings.Individual biclusters are represented by terminal branches. Relationships are derived using a distance measure based on the proportion of shared interactions between significant biclusters and the tree was drawn using the neighbor joining method. The tree is divided into sections that show the higher-level host subsystems, largely derived using the tree structure. Subsystems of  biclusters are colour coded (see key). Biclusters not labelled are those that have been placed in a biologically related group not adjacent on the tree.
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pcbi-1000863-g005: Tree showing the relationship between significant biclusters and higher-level host subsystem groupings.Individual biclusters are represented by terminal branches. Relationships are derived using a distance measure based on the proportion of shared interactions between significant biclusters and the tree was drawn using the neighbor joining method. The tree is divided into sections that show the higher-level host subsystems, largely derived using the tree structure. Subsystems of biclusters are colour coded (see key). Biclusters not labelled are those that have been placed in a biologically related group not adjacent on the tree.

Mentions: Higher-level relationships between biclusters were identified using a distance measure based upon overlap between biclusters. Using the resulting pairwise distances a tree was constructed using the neighbor joining method [37] (see figure 5). This tree has been partitioned into sections, representing 37 biological subsystems within the host cell that are named according to over-represented GO terms, or after a specific protein (see materials and methods for more detail). In the tree representation we can observe subsystems that undergo a complex set of interactions during HIV-1 infection. These have a large number of terminal branches, representing many distinct but related HIV-host interaction combinations, where a single and clear pattern of interaction can not be simply defined, or does not exist, e.g., the cytokine activity subsystem. Conversely, the v-akt subsystem is relatively well defined including just two closely related HIV-host interaction combinations.


Patterns of HIV-1 protein interaction identify perturbed host-cellular subsystems.

MacPherson JI, Dickerson JE, Pinney JW, Robertson DL - PLoS Comput. Biol. (2010)

Tree showing the relationship between significant biclusters and higher-level host subsystem groupings.Individual biclusters are represented by terminal branches. Relationships are derived using a distance measure based on the proportion of shared interactions between significant biclusters and the tree was drawn using the neighbor joining method. The tree is divided into sections that show the higher-level host subsystems, largely derived using the tree structure. Subsystems of  biclusters are colour coded (see key). Biclusters not labelled are those that have been placed in a biologically related group not adjacent on the tree.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2912648&req=5

pcbi-1000863-g005: Tree showing the relationship between significant biclusters and higher-level host subsystem groupings.Individual biclusters are represented by terminal branches. Relationships are derived using a distance measure based on the proportion of shared interactions between significant biclusters and the tree was drawn using the neighbor joining method. The tree is divided into sections that show the higher-level host subsystems, largely derived using the tree structure. Subsystems of biclusters are colour coded (see key). Biclusters not labelled are those that have been placed in a biologically related group not adjacent on the tree.
Mentions: Higher-level relationships between biclusters were identified using a distance measure based upon overlap between biclusters. Using the resulting pairwise distances a tree was constructed using the neighbor joining method [37] (see figure 5). This tree has been partitioned into sections, representing 37 biological subsystems within the host cell that are named according to over-represented GO terms, or after a specific protein (see materials and methods for more detail). In the tree representation we can observe subsystems that undergo a complex set of interactions during HIV-1 infection. These have a large number of terminal branches, representing many distinct but related HIV-host interaction combinations, where a single and clear pattern of interaction can not be simply defined, or does not exist, e.g., the cytokine activity subsystem. Conversely, the v-akt subsystem is relatively well defined including just two closely related HIV-host interaction combinations.

Bottom Line: Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID.Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction.Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) exploits a diverse array of host cell functions in order to replicate. This is mediated through a network of virus-host interactions. A variety of recent studies have catalogued this information. In particular the HIV-1, Human Protein Interaction Database (HHPID) has provided a unique depth of protein interaction detail. However, as a map of HIV-1 infection, the HHPID is problematic, as it contains curation error and redundancy; in addition, it is based on a heterogeneous set of experimental methods. Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID. Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction. The functional cohesiveness of these protein sets was validated using a human protein-protein interaction network, gene ontology annotation and sequence similarity. Next, using a distance measure, we group host protein sets and identify 37 distinct higher-level subsystems. We further demonstrate the biological significance of these subsystems by cross-referencing with global siRNA screens that have been used to detect host factors necessary for HIV-1 replication, and investigate the seemingly small intersect between these data sets. Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection. Moreover, we characterise the patterns of interaction that contribute to these perturbations. Thus, our work disentangles the complex set of HIV-1-host protein interactions in the HHPID, reconciles these with siRNA screens and provides an accessible and interpretable map of infection.

Show MeSH
Related in: MedlinePlus