Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases

Author:

Sperka Tamás1,Miklóssy Gabriella1,Tie Yunfeng2,Bagossi Péter1,Zahuczky Gábor1,Boross Péter31,Matúz Krisztina1,Harrison Robert W.43,Weber Irene T.32,Tözsér József1

Affiliation:

1. Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary

2. Department of Chemistry, Georgia State University, Atlanta, GA, USA

3. Department of Biology, Georgia State University, Atlanta, GA, USA

4. Department of Computer Science, Georgia State University, Atlanta, GA, USA

Abstract

Bovine leukemia virus (BLV) is a valuable model system for understanding human T-lymphotropic virus 1 (HTLV-1); the availability of an infectious BLV clone, together with animal-model systems, will help to explore anti-HTLV-1 strategies. Nevertheless, the specificity and inhibitor sensitivity of the BLV protease (PR) have not been characterized in detail. To facilitate such studies, a molecular model for the enzyme was built. The specificity of the BLV PR was studied with a set of oligopeptides representing naturally occurring cleavage sites in various retroviruses. Unlike HTLV-1 PR, but similar to the human immunodeficiency virus 1 (HIV-1) enzyme, BLV PR was able to hydrolyse the majority of the peptides, mostly at the same position as did their respective host PRs, indicating a broad specificity. When amino acid residues of the BLV PR substrate-binding sites were replaced by equivalent ones of the HIV-1 PR, many substitutions resulted in inactive protein, indicating a great sensitivity to mutations, as observed previously for the HTLV-1 PR. The specificity of the enzyme was studied further by using a series of peptides containing amino acid substitutions in a sequence representing a naturally occurring HTLV-1 PR cleavage site. Also, inhibitors of HIV-1 PR, HTLV-1 PR and other retroviral proteases were tested on the BLV PR. Interestingly, the BLV PR was more susceptible than the HTLV-1 PR to the inhibitors tested. Therefore, despite the specificity differences, in terms of mutation intolerance and inhibitor susceptibility of the PR, BLV and the corresponding animal-model systems may provide good models for testing of PR inhibitors that target HTLV-1.

Publisher

Microbiology Society

Subject

Virology

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