The elucidation of HIV/SIV envelope glycoprotein structure/function will continue to be the major focus of the research supported by this grant during the next funding period. The envelope gene products of HIV and SIV play a critical role in the virus life cycle by mediating virus attachment and entry into the CD4-bearing target cell and also play a role in viral pathogenesis by modulating the immune response of the host. Our current studies have provided new insights into the process of viral entry/membrane fusion and have provided evidence for potential interactions between the cytoplasmic domain of these viruses and components of the cell. These novel observations point the way to three broad areas of continued investigation that will be the focus of the proposed funding period.
The specific aims of this proposal are: 1. To characterize the role of the tryptophan-rich membrane-proximal (TRMP) domain of gp41 in Env-mediated membrane fusion and glycoprotein incorporation into virus. 2. To analyze the topology and structural requirements of the gp41 membrane-spanning domain for virus assembly and entry. 3. To determine the role of sequences within the cytoplasmic domain (CD) of HIV Env in intracellular transport, and viral pathogenesis: Work from several investigators over the past few years has demonstrated that the cytoplasmic domain of gp41 plays several important roles during virus replication and viral pathogenesis in vivo. This region interacts with domains of Gag during assembly, with cell components during intracellular transport, and appears to modulate the fusogenicity of the Env complex both in the cell and within the virion. Nevertheless, the nature of the signals that mediate these multiple phenotypic effects are incompletely understood, and it is the goal of this proposal to define them through genetic, biochemical and in vivo animal model approaches. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033319-16
Application #
7151920
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Young, Janet M
Project Start
1992-09-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2008-11-30
Support Year
16
Fiscal Year
2007
Total Cost
$369,223
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Bhakta, Sushma J; Shang, Liang; Prince, Jessica L et al. (2011) Mutagenesis of tyrosine and di-leucine motifs in the HIV-1 envelope cytoplasmic domain results in a loss of Env-mediated fusion and infectivity. Retrovirology 8:37
Shang, Liang; Hunter, Eric (2010) Residues in the membrane-spanning domain core modulate conformation and fusogenicity of the HIV-1 envelope glycoprotein. Virology 404:158-67
Yue, Ling; Shang, Liang; Hunter, Eric (2009) Truncation of the membrane-spanning domain of human immunodeficiency virus type 1 envelope glycoprotein defines elements required for fusion, incorporation, and infectivity. J Virol 83:11588-98
Vishwanathan, Sundaram A; Thomas, Annick; Brasseur, Robert et al. (2008) Large changes in the CRAC segment of gp41 of HIV do not destroy fusion activity if the segment interacts with cholesterol. Biochemistry 47:11869-76
Vishwanathan, Sundaram A; Thomas, Annick; Brasseur, Robert et al. (2008) Hydrophobic substitutions in the first residue of the CRAC segment of the gp41 protein of HIV. Biochemistry 47:124-30
Shang, Liang; Yue, Ling; Hunter, Eric (2008) Role of the membrane-spanning domain of human immunodeficiency virus type 1 envelope glycoprotein in cell-cell fusion and virus infection. J Virol 82:5417-28
Vishwanathan, Sundaram A; Hunter, Eric (2008) Importance of the membrane-perturbing properties of the membrane-proximal external region of human immunodeficiency virus type 1 gp41 to viral fusion. J Virol 82:5118-26
Micoli, Keith J; Mamaeva, Olga; Piller, Sabine C et al. (2006) Point mutations in the C-terminus of HIV-1 gp160 reduce apoptosis and calmodulin binding without affecting viral replication. Virology 344:468-79
Heil, Marintha L; Decker, Julie M; Sfakianos, Jeffrey N et al. (2004) Determinants of human immunodeficiency virus type 1 baseline susceptibility to the fusion inhibitors enfuvirtide and T-649 reside outside the peptide interaction site. J Virol 78:7582-9
Lin, Xiaoxu; Derdeyn, Cynthia A; Blumenthal, Robert et al. (2003) Progressive truncations C terminal to the membrane-spanning domain of simian immunodeficiency virus Env reduce fusogenicity and increase concentration dependence of Env for fusion. J Virol 77:7067-77

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