Please use this identifier to cite or link to this item:
http://dspace.mediu.edu.my:8181/xmlui/handle/10261/4924| Title: | HIV-1 Protease Dimer Interface Mutations that Compensate for Viral Reverse Transcriptase Instability in Infectious Virions |
| Authors: | Fondo de Investigación Sanitaria (España) Ministerio de Educación y Ciencia (España) Fundación Ramón Areces Ministerio de Sanidad, Servicios Sociales e Igualdad (España) National Institutes of Health (US) Red Española de Investigación en SIDA |
| Keywords: | HIV Reverse transcriptase Protease Retrovirus Fitness |
| Publisher: | Elsevier |
| Description: | Article available at http://dx.doi.org/10.1016/j.jmb.2007.06.073 Mature enzymes encoded within the human immunodeficiency virus type 1 (HIV-1) genome (protease (PR), reverse transcriptase (RT) and integrase (IN)) derive from proteolytic processing of a large polyprotein (Gag-Pol). Gag-Pol processing is catalyzed by the viral PR, which is active as a homodimer. The HIV-1 RT functions as a heterodimer (p66/p51) composed of subunits of 560 and 440 amino acid residues, respectively. Both subunits have identical amino acid sequence, but p51 lacks 120 residues that are removed by the HIV-1 PR during viral maturation. While p66 is the catalytic subunit, p51 has a primarily structural role. Amino acid substitutions affecting the stability of p66/p51 (i.e. F130W) have a deleterious effect on viral fitness. Previously, we showed that the effects of F130W are mediated by p51 and can be compensated by mutation T58S. While studying the dynamics of emergence of the compensatory mutation, we observed that mutations in the viral PR-coding region were selected in HIV clones containing the RT substitution F130W, before the imposition of T58S/F130W mutations. The PR mutations identified (G94S and T96S) improved the replication capacity of the F130W mutant virus. By using a trans-complementation assay, we demonstrate that the loss of p66/p51 heterodimer stability caused by Trp130 can be attributed to an increased susceptibility of RT to viral PR degradation. Recombinant HIV-1 PRs bearing mutations G94S or T96S showed decreased dimer stability and reduced catalytic efficiency. These results were consistent with crystallographic data showing the location of both residues in the PR dimerization interface This work was supported, in part, by Fondo de Investigación Sanitaria (through the “Red Temática de Investigación Cooperativa en SIDA” RD06/006). In addition, work in the CBMSO (Madrid) was supported by grant BIO2003/01175 (Spanish Ministry of Education and Science) and an institutional grant from the Fundación Ramón Areces. Work in the CNM (Majadahonda) was supported by grants SAF2002/626, SAF2003/4987 and SAF2005/3833 (Spanish Ministry of Education and Science), and by the Plan Nacional sobre el SIDA. Work in the UAB was supported by National Institutes of Health grants CA73470 and AI47714 and core facilities of the Birmingham Center for AIDS Research (P30-AI-27767). Support from the Spanish-Hungarian Intergovernmental Science and Technology Cooperation Program (grant HH2005-0020) is acknowledged Peer reviewed |
| URI: | http://dspace.mediu.edu.my:8181/xmlui/handle/10261/4924 |
| Other Identifiers: | Journal of Molecular Biology Vol.372, Issue 2, 14 September 2007, Pages 369-381 0022-2836 (Print) 1089-8638 (Online) http://hdl.handle.net/10261/4924 |
| Appears in Collections: | Digital Csic |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.