Current research topics
Besides the studies on human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) proteins currently we are concentrating on the cloning and biochemical characterization of proteases of additional retroviruses having implication in human diseases (human T-lymphotropic virus type 2 and 3, HTLV-2 and HTLV-3) as well as that of an endogenous retrovirus MSRV (multiple sclerosis-associated retrovirus), LTR retrotransposons (TY1, TY3), and the PR of retrotransposon remnant PEG10 (paternally expressed gene 10), and the cellular dimeric aspartyl protease ASPRV1 (retroviral-like aspartic protease 1).
We recently perform cell culture experiments to study the effects of protease inhibitors on the action of HIV -2. We plan to determine the activity and dimer stability of the currently studied proteases and perform comparative in vitro inhibition profiling of dimeric aspartyl proteases.
Our aim is to identify the structural elements responsible for the differential inhibition of the PRs and we plan the comparative characterization of the specificity of homodimeric (retroviral, retroelement and cellular) proteases in order to identify key similarities and differences in substrate specificity.
Together with the research group of Szilvia Benkő (Department of Physiology, Faculty of Medicine, University of Debrecen) we are studying some members of the NOD-like receptor (NLR) family member proteins having important role in the regulation of innate immune responses. We have recently published homology models for both the monomeric and a homo-heptameric full-length human NLRC5 (NOD-like receptor family CARD domain containing 5) protein and the aim of our recent studies is to correlate biochemical findings with the proposed models.
LRB has also been involved in the application of retroviral-derived vectors in gene therapy. Retroviruses are ideal tools for gene therapy, especially since their life cycle includes a highly efficient integration step.
Previous research topics
One of the major research interests of the LRB is to study the biochemistry and enzymology of retroviral replication, with an emphasis on the function and features of the viral protease (PR). All replication competent retroviruses code for a PR. The function of the mature PR is critical for virion replication. The HIV-1 PR has proved to be an excellent target for antiretroviral therapy of AIDS, and various PR inhibitors are now in clinical use. However, there is a rapid selection of viral variants that are resistant to inhibitors of PR. Comparative studies of various PRs have revealed the common features of their specificity. These studies are expected to aid the rational design of broad-spectrum inhibitors effective against various retroviral proteinases, including the mutant HIV-1 enzymes appearing in drug resistance.
We have previously studied and characterized the PR of the following retrovirues: HIV-1, HIV-2, equine infectious anemia virus (EIAV), human T-cell leukemia virus (HTLV), bovine leukemia virus (BLV), avian myeloblastosis virus (AMV), and human foamy virus (HFV).
Members of the LRB are also involved in other collaborative works. These include studies of the homo- and heteroassociation patterns of MHC and ErbB receptors in collaboration with the research group of Dr. Janos Szollosi (Department of Biophysics, UD). Also, LRB is historically involved in studies on the proteolytic systems of the anterior segment of the eye, in collaboration with the team of Dr. Andras Berta (Department of Ophthalmology, UD). Another collaboration involves characterization of potyviral proteases, in collaboration with Dr. David Waugh (NCI-Frederick, USA).
The specificity of the proteases of eleven retroviruses was studied previously using a series of oligopeptides having single amino acid substitutions in various positions of a naturally occurring cleavage site of HIV-1. The protease set included at least one member from each of the seven genera of the family Retroviridae.