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      Comparative Studies on Retroviral Proteases: Substrate Specificity

      review-article
      Author(s):
      Publication date (Electronic):
      Journal: Viruses
      Publisher: Molecular Diversity Preservation International (MDPI)
      Keywords: retroviral proteases, HIV protease, substrate specificity

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          Abstract

          Exogenous retroviruses are subclassified into seven genera and include viruses that cause diseases in humans. The viral Gag and Gag-Pro-Pol polyproteins are processed by the retroviral protease in the last stage of replication and inhibitors of the HIV-1 protease are widely used in AIDS therapy. Resistant mutations occur in response to the drug therapy introducing residues that are frequently found in the equivalent position of other retroviral proteases. Therefore, besides helping to understand the general and specific features of these enzymes, comparative studies of retroviral proteases may help to understand the mutational capacity of the HIV-1 protease.

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          The discovery of endogenous retroviruses

          Robin Weiss (2006)
          When endogenous retroviruses (ERV) were discovered in the late 1960s, the Mendelian inheritance of retroviral genomes by their hosts was an entirely new concept. Indeed Howard M Temin's DNA provirus hypothesis enunciated in 1964 was not generally accepted, and reverse transcriptase was yet to be discovered. Nonetheless, the evidence that we accrued in the pre-molecular era has stood the test of time, and our hypothesis on ERV, which one reviewer described as 'impossible', proved to be correct. Here I recount some of the key observations in birds and mammals that led to the discovery of ERV, and comment on their evolution, cross-species dispersion, and what remains to be elucidated.
          Article 0 comments Cited 120 times – based on 0 reviews     Review now
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            The p2 domain of human immunodeficiency virus type 1 Gag regulates sequential proteolytic processing and is required to produce fully infectious virions.

            P G Nantermet, Bonnie Kaplan, Fabrice Klein … (1994)
            The proteolytic processing sites of the human immunodeficiency virus type 1 (HIV-1) Gag precursor are cleaved in a sequential manner by the viral protease. We investigated the factors that regulate sequential processing. When full-length Gag protein was digested with recombinant HIV-1 protease in vitro, four of the five major processing sites in Gag were cleaved at rates that differ by as much as 400-fold. Three of these four processing sites were cleaved independently of the others. The CA/p2 site, however, was cleaved approximately 20-fold faster when the adjacent downstream p2/NC site was blocked from cleavage or when the p2 domain of Gag was deleted. These results suggest that the presence of a C-terminal p2 tail on processing intermediates slows cleavage at the upstream CA/p2 site. We also found that lower pH selectively accelerated cleavage of the CA/p2 processing site in the full-length precursor and as a peptide primarily by a sequence-based mechanism rather than by a change in protein conformation. Deletion of the p2 domain of Gag results in released virions that are less infectious despite the presence of the processed final products of Gag. These findings suggest that the p2 domain of HIV-1 Gag regulates the rate of cleavage at the CA/p2 processing site during sequential processing in vitro and in infected cells and that p2 may function in the proper assembly of virions.
            Article 0 comments Cited 75 times – based on 0 reviews     Review now
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              HIV-1 drug resistance mutations: an updated framework for the second decade of HAART.

              Robert Shafer, Jonathan M. Schapiro (2008)
              More than 200 mutations are associated with antiretroviral resistance to drugs belonging to six licensed antiretroviral classes. More than 50 reverse transcriptase mutations are associated with nucleoside reverse transcriptase inhibitor resistance including M184V, thymidine analog mutations, mutations associated with non-thymidine analog containing regimens, multi-nucleoside resistance mutations, and several recently identified accessory mutations. More than 40 reverse transcriptase mutations are associated with nonnucleoside reverse transcriptase inhibitor resistance including major primary and secondary mutations, non-polymorphic minor mutations, and polymorphic accessory mutations. More than 60 mutations are associated with protease inhibitor resistance including major protease, accessory protease, and protease cleavage site mutations. More than 30 integrase mutations are associated with the licensed integrase inhibitor raltegravir and the investigational inhibitor elvitegravir. More than 15 gp41 mutations are associated with the fusion inhibitor enfuvirtide. CCR5 inhibitor resistance results from mutations that promote gp120 binding to an inhibitor-bound CCR5 receptor or CXCR4 tropism; however, the genotypic correlates of these processes are not yet well characterized.
              Article 0 comments Cited 72 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Viruses
                Title: Viruses
                Publisher: Molecular Diversity Preservation International (MDPI)
                ISSN (Electronic): 1999-4915
                Publication date Collection: January 2010
                Publication date (Electronic): 14 January 2010
                Volume: 2
                Issue: 1
                Pages: 147-165
                Affiliations
                Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Egyetem tér 1, Debrecen, Hungary; E-Mail: tozser@ 123456med.unideb.hu ; Tel.: +36-52-416-432; Fax: +36-52-314-989
                Article
                Publisher ID: viruses-02-00147
                DOI: 10.3390/v2010147
                PMC ID: 3185560
                PubMed ID: 21994605
                SO-VID: d46b2ab4-08d8-45bb-b985-3869f2e297dd
                Copyright © © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 7 October 2009
                Date revision received : 12 January 2010
                Date accepted : 13 January 2010
                Categories
                Subject: Review

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: substrate specificity,retroviral proteases,hiv protease
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: substrate specificity, retroviral proteases, hiv protease

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