Effect of transcription peptide inhibitors on HIV-1 replication.
HIV-1 manipulates cellular machineries such as cyclin dependent kinases (cdks) and their cyclin elements, to stimulate virus production and maintain latent infection. Specifically, the HIV-1 viral protein Tat increases viral transcription by binding to the TAR promoter element. This binding event is mediated by the phosphorylation of Pol II by complexes such as cdk9/Cyclin T and cdk2/Cyclin E. Recent studies have shown that a Tat 41/44 peptide derivative prevents the loading of cdk2 onto the HIV-1 promoter, inhibiting gene expression and replication. Here we show that Tat peptide analogs computationally designed to dock at the cyclin binding site of cdk2 have the ability to bind to cdk2 and inhibit the association of cdk2 with the HIV promoter. Specifically, the peptide LAALS dissociated the complex and decreased kinase activity in vitro. We also describe our novel small animal model which utilizes humanized Rag2(-/-)gamma(c)(-/-) mice. This small peptide inhibitor induces a decrease in HIV-1 viral transcription in vitro and minimizes viral loads in vivo.
Van Duyne
Rachel
R
The George Washington University Medical Center, Department of Microbiology, Immunology, and Tropical Medicine, Washington, DC 20037, USA. bcmrvv@gwumc.edu
Cardenas
Jessica
J
Easley
Rebecca
R
Wu
Weilin
W
Kehn-Hall
Kylene
K
Klase
Zak
Z
Mendez
Susana
S
Zeng
Chen
C
Chen
Hao
H
Saifuddin
Mohammed
M
Kashanchi
Fatah
F
D000818:Animals; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication; D038222:gamma-Crystallins / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D010446:Peptide Fragments; C499308:Rag2 protein, mouse; C111139:Tat peptide (37-72), Human immunodeficiency virus 1; D038222:gamma-Crystallins; D054322:tat Gene Products, Human Immunodeficiency Virus; D051357:Cyclin-Dependent Kinase 2