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.
Highlights
Acquired immunodeficiency syndrome (AIDS), caused by HIV1, is responsible for millions of deaths every year
We found that interactions within significant biclusters had a mean of 2.94 supporting publications, while other interactions with human proteins that could potentially be in biclusters have a mean of 2.46 and interactions with all non-biclustered interactions had a mean of 2.29
protein-protein interactions (PPIs) network clustering Integrating human proteins from significant biclusters into a human PPI network, we identified 38 biclusters where the proteins share a greater number of interactions, 24 where the proteins form a bigger largest connected component (LCC) and 38 where the proteins have a smaller average shortest path length than would be expected by random chance
Summary
Acquired immunodeficiency syndrome (AIDS), caused by HIV1, is responsible for millions of deaths every year. HIV-1, like all viruses, must use host-cellular machinery and induce production of viral genomic material, viral proteins and new virions. This hijack and control over host cell processes is mediated by HIV-1 proteins through a complex network of molecular events, including virus-host protein-protein interactions (PPIs) [1]. A major source of HIV-1-host protein interaction data is the HIV-1, Human Protein Interaction Database (HHPID) [1,4,5] This database holds over 5000 interactions involving over 1400 human proteins, curated from primary literature on small-scale protein interaction studies. In the HHPID there are 27 entries describing interaction between the
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