HIV establishes a persistent infection despite vigorous host immune responses. However, studies using attenuated viruses in animal models have shown that protection can be conferred and pathogenesis altered, raising hope that appropriately designed immunogens can elicit protection or attenuate the course of infection. This proposal applies insights gained from studies of the SIV transmembrane envelope protein (TM) to test the hypothesis that the TM ecto- and cytoplasmic domains can be modified rationally to alter pathogenesis and the host immune response.
Two Aims are proposed, each with in vitro and in vivo components.
Aim # 1 - Based on observations that the SIV TM cytoplasmic tail contains endocytosis signals that reduce Env expression on infected cells, these signals will be analyzed and their impact on pathogenesis and the host immune response determined. Preliminary results indicate that viruses with mutations in these signals are profoundly attenuated in nonhuman primates. In vitro, the structure and function of SIV endocytosis signals will be defined and interactions with cellular and viral proteins characterized. In vivo, the effects of mutations in these signals on pathogenesis will be determined in SIV and SHIV models. A primary goal is to determine if viruses lacking endocytosis signals elicit a different immune response, and if this response can be protective.
Aim # 2 - Determinants in the TM ectodomain have been identified that increase the stability of the TM/gp120 interaction and the gp120 content on virions, and in this Aim the effect of this alteration on the host immune response will be determined. In vitro, mutations that increase retention of gp120 will be defined and their mechanism of action determined through genetic and structural approaches. In vivo, inactivated viral particles engineered to express increased levels of gp120 will be used in nonhuman primates to determine if qualitatively different immune responses can be generated, and if this response confers protection or alters the natural history of infection from a pathogenic challenge virus. Collectively these Aims provide novel approaches for structure-based alterations in the SIV TM that will impact on pathogenesis and the host immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049784-04
Application #
6747370
Study Section
Special Emphasis Panel (ZRG1-VACC (02))
Program Officer
Sharma, Opendra K
Project Start
2001-05-15
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
4
Fiscal Year
2004
Total Cost
$778,978
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Del Prete, Gregory Q; Leslie, George J; Haggarty, Beth et al. (2010) Distinct molecular pathways to X4 tropism for a V3-truncated human immunodeficiency virus type 1 lead to differential coreceptor interactions and sensitivity to a CXCR4 antagonist. J Virol 84:8777-89
Reeves, R Keith; Wei, Qing; Fultz, Patricia N (2010) Mobilization of CD34+ progenitor cells in association with decreased proliferation in the bone marrow of macaques after administration of the Fms-like tyrosine kinase 3 ligand. Clin Vaccine Immunol 17:1269-73
Reeves, R Keith; Wei, Qing; Stallworth, Jackie et al. (2009) Systemic dendritic cell mobilization associated with administration of FLT3 ligand to SIV- and SHIV-infected macaques. AIDS Res Hum Retroviruses 25:1313-28
Del Prete, Gregory Q; Haggarty, Beth; Leslie, George J et al. (2009) Derivation and characterization of a simian immunodeficiency virus SIVmac239 variant with tropism for CXCR4. J Virol 83:9911-22
Crooks, Emma T; Jiang, Pengfei; Franti, Michael et al. (2008) Relationship of HIV-1 and SIV envelope glycoprotein trimer occupation and neutralization. Virology 377:364-78
Reeves, R Keith; Fultz, Patricia N (2007) Disparate effects of acute and chronic infection with SIVmac239 or SHIV-89.6P on macaque plasmacytoid dendritic cells. Virology 365:356-68
Byland, Rahel; Vance, Patricia J; Hoxie, James A et al. (2007) A conserved dileucine motif mediates clathrin and AP-2-dependent endocytosis of the HIV-1 envelope protein. Mol Biol Cell 18:414-25
Deneka, Magdalena; Pelchen-Matthews, Annegret; Byland, Rahel et al. (2007) In macrophages, HIV-1 assembles into an intracellular plasma membrane domain containing the tetraspanins CD81, CD9, and CD53. J Cell Biol 177:329-41
Wei, Qing; Stallworth, Jackie W; Vance, Patricia J et al. (2006) Simian immunodeficiency virus (SIV)/immunoglobulin G immune complexes in SIV-infected macaques block detection of CD16 but not cytolytic activity of natural killer cells. Clin Vaccine Immunol 13:768-78
Byland, R; Marsh, M (2005) Trafficking of viral membrane proteins. Curr Top Microbiol Immunol 285:219-54

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