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 ) .
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 .
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 i d 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 . 

ncbi reference sequence ( refseq ) protein accession numbers ; ncbi entrez gene i d 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 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 i d , hiv-1 gene i d , hiv-1 protein accession number , hiv-1 protein name , the interaction keyword , the human tax i d , human gene i d , human protein accession number , human protein name , the pmid(s ) , the modification date and the interaction description . 

( 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 .
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 ) .
( 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 .
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 ) .
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 
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 .
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 .
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 .
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 ) . 

( d ) the interactions and descriptions are linked to the supporting literature in pubmed .
( d ) the interactions and descriptions are linked to the supporting literature in pubmed . by integrating the hiv-1 interaction data into the entrez gene database , researchers benefit from the additional computation ncbi
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 geneexplanationhiv1interactions[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 .
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 . 

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 .
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 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 ) .
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 ( 13,1517 ) .
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 .
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 .
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 .
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 .
 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 . 
INTRODUCTION
DATABASE AND DATA DESCRIPTIONS
DATA DISSEMINATION AND EXPORT
DATA SEARCH, ANALYSIS AND VISUALIZATION TOOLS
VALUE OF THE DATABASE TO THE AIDS RESEARCH COMMUNITY
FUTURE DEVELOPMENTS
FUNDING