Nucleic Acids Research Advance Access originally published online on October 15, 2008
Nucleic Acids Research 2009 37(Database issue):D417-D422; doi:10.1093/nar/gkn708
Nucleic Acids Research, 2009, Vol. 37, Database issue D417-D422
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Human immunodeficiency virus type 1, human protein interaction database at NCBI
William Fu1,*,
Brigitte E. Sanders-Beer1,
Kenneth S. Katz2,
Donna R. Maglott2,
Kim D. Pruitt2 and
Roger G. Ptak1
1Southern Research Institute, Frederick, MD 21701 and 2National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA
*To whom correspondence should be addressed. Tel: +1 301 694 3232, ext.217; Fax: +1 301 694 7223; Email: fu{at}southernresearch.org
Received August 29, 2008. Revised September 26, 2008. Accepted September 29, 2008.
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ABSTRACT
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The ‘Human Immunodeficiency Virus Type 1 (HIV-1), Human
Protein Interaction Database’, available through the National
Library of Medicine at
www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions,
was created to catalog all interactions between HIV-1 and human
proteins published in the peer-reviewed literature. The database
serves the scientific community exploring the discovery of novel
HIV vaccine candidates and therapeutic targets. To facilitate
this discovery approach, the following information for each
HIV-1 human protein interaction is provided and can be retrieved
without restriction by web-based downloads and ftp protocols:
Reference Sequence (RefSeq) protein accession numbers, Entrez
Gene identification numbers, brief descriptions of the interactions,
searchable keywords for interactions and PubMed identification
numbers (PMIDs) of journal articles describing the interactions.
Currently, 2589 unique HIV-1 to human protein interactions and
5135 brief descriptions of the interactions, with a total of
14 312 PMID references to the original articles reporting the
interactions, are stored in this growing database. In addition,
all protein–protein interactions documented in the database
are integrated into Entrez Gene records and listed in the ‘HIV-1
protein interactions’ section of Entrez Gene reports.
The database is also tightly linked to other databases through
Entrez Gene, enabling users to search for an abundance of information
related to HIV pathogenesis and replication.
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INTRODUCTION
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The year 2008 marks the 27th anniversary of the first case report
of a new disease today known as acquired immunodeficiency syndrome
(AIDS), whose etiological agent is human immunodeficiency virus
type 1 (HIV-1) (
1). An estimated 38.6 million people are now
living with HIV or AIDS worldwide, and nearly 11 000 people
are infected by HIV daily (Joint United Nations Programme on
HIV/AIDS/World Health Organization). Since the documentation
of the first AIDS case, numerous efforts have focused on vaccine
and antiviral drug discovery and development, on identifying
measures to prevent HIV transmission, on understanding HIV pathogenesis
and the associated host immune responses, and on defining the
interactions of HIV-1 proteins with human host cell proteins.
The latter is crucial to understanding the individual steps
of HIV-1 replication and pathogenesis, and provides an essential
foundation for the development of safe and effective therapeutic
and prevention strategies to combat AIDS. As a result of these
efforts, thousands of published articles have addressed the
interaction of HIV-1 proteins with human host proteins. However,
each individual publication addresses only one or a few HIV
protein–host protein interactions making it cumbersome
to collect information on all interactions for one particular
HIV or cellular protein.
The Division of Acquired Immunodeficiency Syndrome (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) recognized the need for a searchable platform to catalog the interactions of individual HIV proteins with host cell proteins. Therefore, the development of an HIV-1, Human Protein Interaction Database was initiated in collaboration with Southern Research Institute and the National Center for Biotechnology Information (NCBI).
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DATABASE AND DATA DESCRIPTIONS
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Development of the HIV-1, Human Protein Interaction Database
from the peer-reviewed scientific literature available in PubMed
was a 7-year effort starting in 2000. A short communication
detailing the development of the database and including a visualization
of the HIV-1, human protein interaction network has been published
recently (
2). Briefly, more than 100 000 journal abstracts and
publications were identified and screened for original research
describing interactions between HIV-1 and human host proteins.
In addition, new literature is routinely reviewed to identify
interactions described in current publications. Review of publications
by scientific curator staff is organized by individual HIV-1
proteins and catalogued into an Access database by extracting
the interaction information from the continuous text. As review
of individual interactions is completed, data are provided to
NCBI incrementally as a set of comprehensive tab-delimited text
files and loaded to a MS SQL Server 2005 database. The loading
process validates the RefSeq, PubMed and NCBI Entrez Gene identifiers.
Validated interaction data are integrated into appropriate records
in Entrez Gene and provided as custom reports and downloads
per HIV-1 protein through the ‘Reports and Downloads’
tools at
http://www.ncbi.nlm.nih.gov/projects/RefSeq/HIVInteractions/.
The complete dataset is also available for ftp (
ftp://ftp.ncbi.nih.gov/gene/GeneRIF/hiv_interactions.gz).
An update to the database released on 13 November 2007, which
included the interaction data set for the HIV-1 Env proteins,
marked the milestone of completion of the comprehensive ‘HIV-1,
Human Protein Interaction Database’ based on original
research articles published since 1984. Updates to the database
based on interactions described in new scientific reports will
be released on a recurring basis.
The goal in developing this database was to provide scientists in the field of HIV/AIDS research a concise, yet detailed, summary of all known interactions between HIV-1 and host cell proteins and it has therefore been designed to track the following information for each protein–protein interaction identified in the literature:
- NCBI Reference Sequence (RefSeq) protein accession numbers;
- NCBI Entrez Gene ID numbers;
- Brief description of the protein–protein interaction;
- Keywords to support searching for interactions;
- National Library of Medicine (NLM) PubMed identification numbers (PMIDs) for all journal articles describing the interaction.
The information compiled into
the database is made publicly available through the NCBI website.
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DATA DISSEMINATION AND EXPORT
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The purpose of the database is to serve as a central interactive
interface for viewing an ensemble of the known interactions
between individual HIV-1 proteins and human proteins. The HIV-1,
Human Protein Interaction Database home page (
http://www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions/)
enables users to simultaneously view and download a variety
of reports detailing interactions for each HIV-1 protein. The
database is structured by initial searches for the nine HIV
proteins (e.g. Gag, Pol, Env, Tat, Rev, Nef, Vif, Vpr and Vpu),
listed in the top right panel of the home page. An alphabetical
report of all interacting human proteins is accessed by following
the link for any of the HIV-1 proteins. The HIV-1 proteins can
also be searched based on their components, for example HIV-1
Envelope can be searched either for the entire protein gp160,
or separately for the gp120 surface glycoprotein or the gp41
transmembrane protein, which result from proteolytic cleavage
of gp160. The HIV-to-human protein interactions are categorized
by 43 interaction keywords (e.g.
activates, associates with, binds, cleaves, complexes with, deglycosylates, inhibits, modulates, upregulates, etc.). A query interface allows for searching of
the database to identify cellular proteins that have a specific
type of interaction with a viral protein based on these keywords.
The report can be customized to categories of interest by selecting
a specific HIV protein and interaction keywords from the drop
down menus. Reports can be viewed as a web page, or downloaded
as a text file for later use. In addition, to help facilitate
the retrieval of related data, links to other database resources,
such as the Database of Interacting Proteins (DIP;
3), the Molecular
INTeraction Database (MINT;
4), the Binding Database (
5) and
the Los Alamos National Laboratories (LANL) HIV Databases (
6),
are provided on the home page.
Figure 1 depicts the report and search interface page for the HIV-1 Gag polyprotein and its cleavage products. As mentioned earlier, the drop down menus (Figure 1A) allow for the selection of data related to the individual Gag cleavage products (e.g. matrix, capsid, nucleocapsid, p1 and p6) and also facilitate searching by specific keywords (e.g. associates with, binds and inhibits) that represent the relationship between the viral proteins and the interacting human proteins (Figure 1B). Reports can either be viewed online or downloaded in ASCII format and contain the HIV-1 Tax ID, HIV-1 Gene ID, HIV-1 protein accession number, HIV-1 protein name, the Interaction Keyword, the human Tax ID, human Gene ID, human protein accession number, human protein name, the PMID(s), the modification date and the interaction description.
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Figure 1. Partial report page of HIV-1 Gag interactions with human proteins. (A) All or part of the interaction data available for an HIV-1 protein can be accessed using the drop down menus. (B) The interacting relationship between HIV-1 and human proteins is reported below the menus. The figure illustrates a query section to display all interactions catalogued for the HIV-1 Pr55 (Gag) protein. The display is sorted alphabetically by the interaction term. For example, the first two interactions shown are: (i) Pr55 (Gag) protein associates with ATP-binding cassette, sub-family E, member 1; and (ii) Pr55 (Gag) protein binds to adaptor-related protein complex 2, alpha 1 subunit isoform 1. (C) Further down, the display shows the association of HIV-1 matrix and p6 with the mitogen-activated protein kinase 1 (MAPK1). (D) The arrow points to the link for the Entrez Gene reports (the green ‘G’ icon).
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DATA SEARCH, ANALYSIS AND VISUALIZATION TOOLS
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Currently, the database is composed of 1434 human genes encoding
1448 proteins that directly (e.g.
bind, inhibit) or indirectly
(e.g.
upregulate, modify) interact with HIV-1 proteins. It was
found that the majority of the interactions reported are indirect
(68%), whereas the rest are direct (
2). In addition, the database
comprises 2589 unique HIV-1 to human protein interactions and
5135 brief descriptions of the interactions, with a total of
14 312 PMID references to the original articles that reported
the interactions. A network of links to supporting literature
and cross-references allows users to navigate concomitantly
between this database and other resources at NCBI (
7), such
as Entrez Gene (
8), RefSeq (
9) and PubMed. Reports in Entrez
Gene that contain HIV-1 interaction data can be retrieved with
the query ‘hiv1interactions’[Properties] AND ‘Homo
sapiens’[Organism]. Navigation to a target human protein
interaction can be accomplished via one of two primary routes:
an ‘HIV-1, Human Protein Interaction Database’ search
or an Entrez Gene text query. For illustration purposes, two
search scenarios for the signaling protein mitogen-activated
protein kinase 1 (MAPK1), which displays a high magnitude of
interactions with ten different HIV-1 proteins, are provided
subsequently.
Search scenario 1 begins with an ‘HIV-1, Human Protein Interaction Database’ search. To view interactions between MAPK1 and Gag or its cleavage products, users may select ‘gag’ in the horizontal selection bar on the top right panel of the database home page (http://www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions/), which makes a direct link to the illustration as shown in Figure 1. Using the scroll down mouse menu, MAPK1 can be identified since interacting proteins reported in each interaction session (e.g. associates with and binds in Figure 1B) are alphabetic. As a searching result, MAPK1 is involved in the process of matrix and p6 phosphorylation (Figure 1C). Users may click on links to Entrez Gene (the green ‘G’ icon; Figure 1D) to view the MAPK1 full report.
Search scenario 2 begins with a text-based search in Entrez Gene. Entrez Gene (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene) is NCBI's database for gene-specific information. Users may begin with the following query: mitogen-activated protein kinase 1[title] AND Homo sapiens [organism]. The entries (e.g. MAPK1 and MAPK1IP1L) identified with the query are displayed on the Entrez Gene results page. Adding ‘AND hiv1interactions[prop]’ to the query restricts the results to only those entries that have HIV-1 interaction data, and in this example returns a single match to the MAPK1 gene report shown in Figure 2. The protein–protein interactions associated with MAPK1 are listed on the Entrez Gene report page in the ‘HIV-1 protein interactions’ section (Figure 2); a link to this section is included in the right column ‘Table of Contents’ provided on the full report display (Figure 2A). Individual HIV-1 proteins (e.g. Envelope surface glycoprotein gp120) that interact with MAPK1 are listed (Figure 2B) along with brief descriptions of the interactions (Figure 2C) and links to the supporting literature in PubMed (Figure 2D).
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Figure 2. Partial Entrez Gene report page for MAPK1. (A) The report page includes a link to the ‘HIV-1 protein interactions’ section in the Table of Contents. (B) The ‘HIV-1 protein interactions’ section shows the interaction of MAPK1 with different HIV-1 proteins. (C) Summary descriptions of the interactions are provided. (D) The interactions and descriptions are linked to the supporting literature in PubMed.
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By integrating the HIV-1 interaction data into the Entrez Gene
database, researchers benefit from the additional computation
NCBI provides. For example, from the ‘HIV-1, Human Protein
Interaction Database’ home page, there are automatic queries
provided to PubMed and the NCBI sequence databases for recent
records of interest. Via Entrez Gene, information can be easily
obtained about genomic context, pathway membership and protein
domain structure. The representative Entrez Gene search strategies
summarized in the following table demonstrate the strength of
the data integration and provide examples of how specific subsets
of data can be retrieved:
| Query to Enter in Entrez Gene |
Explanation |
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| hiv1interactions[prop] AND human[organism] AND 5[chr] AND 1000000:12000000[Base Position] |
Genes for which products interact with HIV-1 proteins, based on chromosome location. The value before [chr] gives the chromosome, and the range separated by : gives the location in base pairs on that chromosome. |
| hiv1interactions[prop] AND human[organism] AND cytoplasm*[go] |
Genes for which products interact with HIV-1 proteins, and are coded by the GO Consortium with at least one term starting with ‘cytoplasm’. |
| hiv1interactions[prop] AND human[organism] AND immunoglobulin[Domain Name] |
Genes for which products interact with HIV-1 proteins, and are calculated by NCBI's Conserved Domain Database group as having an immunoglobulin domain. |
| hiv1interactions[prop] AND human[organism] AND (kegg OR reactome) |
Genes for which products interact with HIV-1 proteins and for which pathways data are available from the KEGG or Reactome groups. |
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Data visualization can be accomplished in multiple ways utilizing the information stored in this database. Figure 3 shows an example of data visualization using biological process Gene Ontology (GO) terms (10, http://www.geneontology.org) and individual HIV-1 proteins. This bar chart also demonstrates that a large portion of interactions catalogued in the database are associated with the HIV envelope surface (gp120) and Tat proteins. The human cellular proteins interacting with HIV span a wide variety of functional categories, (e.g. signal transduction, protein metabolism, development, etc.) with an overrepresentation of interactions between Tat and cellular proteins involved in transcription. In addition, envelope and Tat proteins also have a high number of interactions with proteins representing multiple biological processes.
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Figure 3. Distribution of interactions based on biological process Gene Ontology (GO) terms and individual HIV-1 proteins. The x-axis shows the individual HIV-1 structural proteins Gag, Pol and Env and their cleavage products, and the regulatory and accessory HIV-1 proteins, Tat, Rev, Nef, Vpu, Vpr and Vif. The y-axis displays the number of interacting human proteins. The various colors represent the biological process categories according to GO terms.
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VALUE OF THE DATABASE TO THE AIDS RESEARCH COMMUNITY
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The HIV-1, Human Protein Interaction Database represents an
important step towards a more detailed understanding of HIV-1
replication and pathogenesis. A recent example of the value
of the database includes the work of Brass
et al. (
11,
12), who
used the database as a tool to help analyze and categorize human
proteins required for HIV-1 replication. Similarly, in order
to support their analysis of human–pathogen protein–protein
interactions, Dyer
et al. (
13) were able to use a subset of
the HIV-1 interaction data that has been incorporated into the
Biomolecular Interaction Network Database (BIND;
14). Systematic
mapping of human–pathogen protein–protein interactions
has recently been studied in detail and such maps have revealed
global and local networks that relate to known biological properties.
Studies have indicated that both viral and bacterial proteins
tend to interact with hubs (proteins with many interacting partners)
and bottlenecks (proteins that are central to many pathways
in the network) in human–pathogen protein–protein
interaction networks (
13,
15–17). Development of such global
and local pathway networks by utilizing the information provided
in the HIV-1, Human Protein Interaction Database will provide
additional insights into HIV-1 replication and disease mechanisms
at a systems biology level. These networks may reconfirm and
extend known pathways, as well as uncover previously unknown
pathway components. In addition, these networks may serve as
a starting point for a systems biology modeling of the development
of effective therapeutic and prophylactic interventions.
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FUTURE DEVELOPMENTS
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The content, website display and bulk reporting from the ‘HIV-1,
Human Protein Interaction Database’ will be continuously
updated to keep the database populated with interactions newly
reported in the literature. Current efforts are also focused
on incorporating these data into Canada's Biomolecular Object
Network Database (BOND) (
http://bond.unleashedinformatics.com;
successor to BIND;
14), a database cataloguing the interactions
between all known cellular proteins. Feedback with respect to
the ‘HIV-1, Human Protein Interaction Database’,
or any data contained therein can be provided by using the ‘Write
to the Help Desk’ link at the bottom of the database and
Entrez Gene web pages.
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FUNDING
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National Institutes of Health, National Institute of Allergy
and Infectious Diseases, Division of AIDS (N01-AI-05415 and
N01-AI-70042 to W.F., B.E.S.-B. and R.G.P.); Intramural Research
Program of the National Institutes of Health, National Library
of Medicine (to K.S.K., D.R.M. and K.D.P.). Funding for open
access charges: Southern Research Institute.
Conflict of interest statement. None declared.
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ACKNOWLEDGEMENTS
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We thank Dr Roger Miller and Dr Carl Dieffenbach, NIH/NIAID/DAIDS,
for discussions and intellectual input throughout this project;
Dr Mikhail Rozanov, NCBI, for support in updating the HIV-1
RefSeq record; Joel Gillman, NCBI, for providing database support;
and Dr David Robertson and Dr John Pinney, University of Manchester,
UK, for help with
Figure 3.
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Footnotes
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Present address: Brigitte E. Sanders-Beer, BIOQUAL, Inc., Rockville,
MD 20850 USA
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