Therapeutic targets for HIV-1 infection in the host proteome.
BACKGROUND
Despite the success of HAART, patients often stop treatment due to the inception of side effects. Furthermore, viral resistance often develops, making one or more of the drugs ineffective. Identification of novel targets for therapy that may not develop resistance is sorely needed. Therefore, to identify cellular proteins that may be up-regulated in HIV infection and play a role in infection, we analyzed the effects of Tat on cellular gene expression during various phases of the cell cycle.


RESULTS
SOM and k-means clustering analyses revealed a dramatic alteration in transcriptional activity at the G1/S checkpoint. Tat regulates the expression of a variety of gene ontologies, including DNA-binding proteins, receptors, and membrane proteins. Using siRNA to knock down expression of several gene targets, we show that an Oct1/2 binding protein, an HIV Rev binding protein, cyclin A, and PPGB, a cathepsin that binds NA, are important for viral replication following induction from latency and de novo infection of PBMCs.


CONCLUSIONS
Based on exhaustive and stringent data analysis, we have compiled a list of gene products that may serve as potential therapeutic targets for the inhibition of HIV-1 replication. Several genes have been established as important for HIV-1 infection and replication, including Pou2AF1 (OBF-1), complement factor H related 3, CD4 receptor, ICAM-1, NA, and cyclin A1. There were also several genes whose role in relation to HIV-1 infection have not been established and may also be novel and efficacious therapeutic targets and thus necessitate further study. Importantly, targeting certain cellular protein kinases, receptors, membrane proteins, and/or cytokines/chemokines may result in adverse effects. If there is the presence of two or more proteins with similar functions, where only one protein is critical for HIV-1 transcription, and thus, targeted, we may decrease the chance of developing treatments with negative side effects.
Liang
Winnie S
WS
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA. wliang@tgen.org
Maddukuri
Anil
A
Teslovich
Tanya M
TM
de la Fuente
Cynthia
C
Agbottah
Emmanuel
E
Dadgar
Shabnam
S
Kehn
Kylene
K
Hautaniemi
Sampsa
S
Pumfery
Anne
A
Stephan
Dietrich A
DA
Kashanchi
Fatah
F
D001483:Base Sequence; D002478:Cells, Cultured; D016193:G1 Phase; D020869:Gene Expression Profiling; D015696:Gene Products, tat / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020543:Proteome; D016196:S Phase; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D011506:Proteins; D020543:Proteome; D054322:tat Gene Products, Human Immunodeficiency Virus