Cutting edge: a short polypeptide domain of HIV-1-Tat protein mediates pathogenesis.
HIV-1 encodes the transactivating protein Tat, which is essential for virus replication and progression of HIV disease. However, Tat has multiple domains, and consequently the molecular mechanisms by which it acts remain unclear. In this report, we provide evidence that cellular activation by Tat involves a short core domain, Tat21-40, containing only 20 aa including seven cysteine residues highly conserved in most HIV-1 subtypes. Effective induction by Tat21-40 of both NF-kappaB-mediated HIV replication and TAR-dependent transactivation of HIV-long terminal repeat indicates that this short sequence is sufficient to promote HIV infection. Moreover, Tat21-40 possesses potent angiogenic activity, further underscoring its role in HIV pathogenesis. These data provide the first demonstration that a 20-residue core domain sequence of Tat is sufficient to transactivate, induce HIV replication, and trigger angiogenesis. This short peptide sequence provides a potential novel therapeutic target for disrupting the functions of Tat and inhibiting progression of HIV disease.
Boykins
R A
RA
Laboratory of Parasitic Biology and Biochemistry, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Mahieux
R
R
Shankavaram
U T
UT
Gho
Y S
YS
Lee
S F
SF
Hewlett
I K
IK
Wahl
L M
LM
Kleinman
H K
HK
Brady
J N
JN
Yamada
K M
KM
Dhawan
S
S
D000482:Allantois / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D002642:Chick Embryo; D002823:Chorion / Q000276:immunology; D003545:Cysteine / Q000235:genetics / Q000276:immunology; D003588:Cytopathogenic Effect, Viral / Q000276:immunology; D015696:Gene Products, tat / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000276:immunology; D015497:HIV-1 / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000821:virology; D016297:Mutagenesis, Site-Directed; D018919:Neovascularization, Physiologic / Q000276:immunology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology*; D012514:Sarcoma, Kaposi / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D014775:Virus Activation / Q000276:immunology; D014779:Virus Replication / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; D003545:Cysteine