This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Current studies for interfering with the life cycle of the human immunodeficiency virus type 1 (HIV-1) are limited to a few targets that control viral replication (reverse transcriptase) and polyprotein processing (viral protease). In addition, the emergence of drug resistant mutant HIV-1 viruses, and lack of an effective vaccine to protect against HIV infection, suggests that the current antiviral efforts should be expanded by combining those antiviral agents with other novel approaches to effectively control the virus. To this end, theHIV-1 Vpu offers another critical target for anti-HIV therapy. The HIV-1 viral protein U (Vpu) is an 80-82 amino acid long integral membrane phosphoprotein with critical roles in: 1) the maturation, secretion and release of mature progeny virions from infected cells, 2) the degradation of the CD4 receptor when complexed with the gp160 viral envelope glycoprotein in the endoplasmic reticulum; and 3) the export of the viral capsid proteins from the infected cell. The virion maturation and release function of Vpu has been mapped to the amino terminal transmembrane domain of the protein which appears to oligomerize into an ion channel, while the carboxyl_-terminal cytoplasmic domain of Vpu is important for inducing the rapid and selective degradation of CD4 receptor from inhibitory complexes with the HIV-1 gp160 in the endoplasmic reticulum of the cell. Thus, the HIV-1 Vpu is an important protein target for novel drug intervention against HIV-1 infection and AIDS. There is evidence that Vpu is localized predominantly to the endoplasmic reticulurn or Golgi region based on immunolocalization studies and results showing interaction between Vpu and CD4-gp160 complexes in this region of the cell. However, no comprehensive studies have been done to determine the role or specificity of Vpu localization to its function. Although Vpu is characterized as a type 1 integral membrane protein, the investigators have identified a conserved tetrapeptide sequence at the carboxylterminal end of Vpu with the consensus IND/EDL, that conforms to the consensus endoplasmic reticulum retention signal sequence, XDEL (X is any amino acid), within the family of resident endoplasmic reticulum luminal glucose-regulated chaperone protein BiP (GRP78). Furthermore, although previous studies have compared the HIV-1 Vpu with the influenza virus MZ ion channel protein, no studies have yet determined a role for Vpu in modulating [Ca2+]i fluxes in the endoplasmic reticulum of the cell, the site of Vpu-induced HIV-1 maturation and CD4 degradation, and the location of chaperone-mediated proper folding of cellular and viral proteins during protein translation. The investigators propose testing the following hypothesis: 1) that the targeting of the HIV-1 Vpu protein to the endoplasnuc reticulum (ER) of the cell is mediated through a well-conserved ER-like localization sequence, consensus Ile/Val-Asp/Glu-Asp-Leu (the I/V-D/E-D-L motif), at the Carboxyl-terminal end of the protein; and 2) that localization of Vpu to the ER is important for a role of Vpu in modulating Ca2+ concentration levels within the ER or the cell. Results from this study may provide new insights into the molecular mechanism of Vpu and potentially lead to new treatment modalities against HIV-1 and AIDS.
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