Abstract

Objectives of this proposal are: 1. To determine the structure of the cis-acting regulatory sequences in the HTLV-III LTR that respond to virus-induced trans-acting regulatory factors. HTLV-III enhancers, promoters and positive as well as negative regulatory sequences will be investigated. 2. Analysis of the sequences in the HTLV-III genome that encode the signals that induce the trans-acting regulatory factors in HTLV-III infected cells. Insertion/deletion mutants in an infectious HTLV-III provirus will be made. Vectors designed to express the virally encoded proteins singly or in groups will be made. 3. The proteins encoded by the HTLV-III genome will be investigated using antisera raised to synthetic peptides and to proteins produced by open reading frame expression vectors. Emphasis will be placed on detection of proteins that might be encoded by the SOR, env-lor, and 3' orf regions. 4. Characterization of HTLV-III encoded mRNA species. Donor-acceptor sites of mRNA splicing will be mapped, cDNA libraries will be constructed, and the coding capacity of the cDNA mRNAs determined. 5. The effect of HTLV-III infection on the expression of host genes will be investigated. Studies will include investigation of alterations in the regulation of mRNA corresponding to the IL1, IL2, IL2 receptor and T-cell receptor genes, investigation of the abundance of certain protooncogene sequences (c-myc, c-myb, c-fos). Libraries of cDNA will be prepared that contain sequences corresponding to genes that are either positively or negatively regulated upon HTLV-III infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028785-07
Application #
3143338
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1989-05-01
Project End
1994-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Hwang, William C; Lin, Yaqiong; Santelli, Eugenio et al. (2006) Structural basis of neutralization by a human anti-severe acute respiratory syndrome spike protein antibody, 80R. J Biol Chem 281:34610-6
Tarnovitski, Natalia; Matthews, Leslie J; Sui, Jianhua et al. (2006) Mapping a neutralizing epitope on the SARS coronavirus spike protein: computational prediction based on affinity-selected peptides. J Mol Biol 359:190-201
Sui, Jianhua; Li, Wenhui; Roberts, Anjeanette et al. (2005) Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants. J Virol 79:5900-6
Gennari, Francesca; Mehta, Smita; Wang, Yang et al. (2004) Direct phage to intrabody screening (DPIS): demonstration by isolation of cytosolic intrabodies against the TES1 site of Epstein Barr virus latent membrane protein 1 (LMP1) that block NF-kappaB transactivation. J Mol Biol 335:193-207
Sui, Jianhua; Li, Wenhui; Murakami, Akikazu et al. (2004) Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci U S A 101:2536-41
Bai, Jirong; Sui, Jianhua; Zhu, Rui Ying et al. (2003) Inhibition of Tat-mediated transactivation and HIV-1 replication by human anti-hCyclinT1 intrabodies. J Biol Chem 278:1433-42
Mhashilkar, A M; Doebis, C; Seifert, M et al. (2002) Intrabody-mediated phenotypic knockout of major histocompatibility complex class I expression in human and monkey cell lines and in primary human keratinocytes. Gene Ther 9:307-19
Ogueta, S B; Yao, F; Marasco, W A (2001) Design and in vitro characterization of a single regulatory module for efficient control of gene expression in both plasmid DNA and a self-inactivating lentiviral vector. Mol Med 7:569-79
Marasco, W A (2001) Intrabodies as antiviral agents. Curr Top Microbiol Immunol 260:247-70
Li, X; Multon, M C; Henin, Y et al. (2000) Upregulation of the apoptosis-associated protein Grb3-3 in HIV-1-infected human CD4(+) lymphocytes. Biochem Biophys Res Commun 276:362-70

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