Regulation of intracellular human immunodeficiency virus type-1 protease activity.
The maturation of HIV-1 virions is accomplished through the proteolytic cleavage of Gag and GagPol precursor polyproteins by the viral-encoded protease (PR). Since virions are assembled from unprocessed polyproteins, the intracellular activation of PR must be limited. An experimental system was established that allows the investigation of the intracellular regulation of PR activity. By expressing Gag in trans with the GagPol precursor, downregulation of the intracellular PR activity associated with GagPol was demonstrated. Inhibition of PR activity was dependent upon the context of PR expression. Sequences capable of mediating this inhibition were localized to capsid. A mechanism through which Gag regulates PR activity is proposed whereby the disproportionate synthesis of Gag inhibits the activation of PR in the cytoplasm. Further elucidation of the mechanism of intracellular inhibition of PR activity may facilitate the development of novel PR inhibitors capable of inhibiting viral replication in vivo.
Gatlin
J
J
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425-2230, USA.
Arrigo
S J
SJ
Schmidt
M G
MG
D000595:Amino Acid Sequence; D002457:Cell Extracts; D015536:Down-Regulation; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism*; D015488:HIV Antigens / Q000235:genetics / Q000378:metabolism; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D019251:Nucleocapsid / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus
D002457:Cell Extracts; D015683:Gene Products, gag; D015488:HIV Antigens; D011498:Protein Precursors; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; C083002:p6 gag protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus; C091950:pr160 gag-pol precursor protein, Human immunodeficiency virus 1; D016333:HIV Protease