The Human Immunodeficiency Virus Type l (HIV-l) is a complex retrovirus that expresses at least 9 different genes in a temporally-regulated manner. The viral protein Rev (regulator of expression of the virion) regulates the expression of viral late genes, necessary for virion production. Rev is absolutely required for HIV- l replication: Proviruses that lack Rev function remain transcriptionally active, but fail to generate new viral particles. Studies of other complex retroviruses have revealed that Rev-like regulatory proteins are a common feature of lentiviruses as well as HTLV I. The studies proposed here will focus on characterizing the functional interactions required for the in vivo function of HIV- l Rev and related viral regulatory proteins. Using a phylogenetic approach to identify and characterize the common features of this family of post-transcriptional regulatory proteins, it will be possible to define the minimal essential functions required by all Rev- like transactivators. The most common feature of this class of viral regulatory proteins is a functional effector domain which interacts with cellular cofactor(s) facilitating function. This proposal aims to determine the essential requirements of functional Rev-like effector domains by identifying and characterizing these domains from the family of identified Rev-like viral regulatory proteins. Functional effector domains can be identified by their ability to restore the function of an effector domain mutant of HIV-l Rev by direct fusion. The interactions between the effector domain and endogenous cellular cofactor(s) will be characterized in vivo using a nuclear and effector domain specific cross-species competition assay. Effector domains in endogenous proteins will be identified using an effector domain complementation system, employing a cell line generated to allow selection of a complemented effector domain mutant of HIV- l Rev. A third functional region recently identified in both HIV-1 Rev and HTLV-I Rex by complementation studies will be characterized which will also determine if this activity is a common feature of the members of the family of Rev-like transactivators. Understanding these interactions should facilitate the characterization of cellular factors involved in the function of Rev-like transactivators and could allow the identification of endogenous Rev-like proteins. This basic knowledge should lay the groundwork for novel therapeutic approaches targeting Rev function and aimed at delaying the onset of AIDS in infected individuals. From a clinical perspective, Rev is an attractive target for directed therapy because it is absolutely required for viral replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI035477-01A2
Application #
2071161
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1994-08-01
Project End
1999-04-30
Budget Start
1994-08-01
Budget End
1995-04-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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