Research
Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy
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* Corresponding author: Andrea Savarino andrea.savarino@iss.it
- † Equal contributors
1 BIOQUAL, Inc 9600 Medical Center Drive, Rockville, MD 20850, USA
2 Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy
3 Dipartimento di Chimica e Tecnologia del Farmaco, Facoltà di Farmacia, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy
4 CNAIDS, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy
5 Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Retrovirology 2010, 7:21 doi:10.1186/1742-4690-7-21
Published: 16 March 2010Additional files
Structural alignment of the integrase catalytic core domains (IN CCDs) HIV-1 subtype B (PDB: 1BL3) and SIVmac251 (PDB: 1C6V). The alignment was conducted on structures deposited in the NCBI database using the VAST algorithm embedded in the website. The structures were then visualised using Cn 3D v. 4.1 (available freely from NCBI). The video was created using SnagIt (TechSmith Corporation Okemos, MI). The HIV-1 and SIVmac251 CCDs are shown in violet and blue, respectively. The active site is shown by the highly conserved catalytic residues D64, D116 and E152 (presented in yellow) and by the Mg2+ ion coordinated by D64 and D116 in the 1BL3 structure. The flexible loop (residues 140-151) is not present in the alignment, due to its variable conformation that may not correspond to that adopted in vivo when the IN CCD is complexed with proviral DNA. The corresponding sequence alignment is shown in Fig. 5.
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Additional file 2:
Correlation between inhibition of p24 production and inhibition of syncytium formation in acutely HIV-1-infected CEMx174 cells. Cells were infected with HIV-1 (IIIB), washed and incubated for five days in the presence or absence of a range of concentrations of raltegravir in a 96-well plate. HIV-1 p24 was quantified in supernatants by commercially available ELISA kits. The numbers of syncytia per well were determined by light microscopy in blinded fashion. Data from one representative experiment are shown and presented as the percentage of inhibition occurring at each of the tested concentrations of raltegravir. The concentrations to which the different data points refer are indicated by arrows in the graph. The solid line is the line best fitting the data points, as calculated by the least-squares method. Dashed lines mark the 95% confidence limits of the regression line. Statistical analysis reported an extremely significant correlation between the percentage-of-inhibition values calculated by the two different methods (r = 0.98; P = 0.0003; t-test for correlation).
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Additional file 3:
Sequence alignment of the integrase catalytic core domains from several lentiviruses. For the sequences adopted, see caption of Figure 6.
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Additional file 4:
Three-dimensional coordinates of a theoretical model for raltegravir docking at the SIVmac251 integrase/proviral DNA interface. Three-dimensional coordinates of a theoretical model for raltegravir docking at the SIVmac251 integrase/proviral DNA interface
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Additional file 5:
IFD binding mode of raltegravir at the SIVmac251 catalytic site in complex with proviral DNA. Molecular surfaces are shown for IN (gray), catalytic loop (residues 140-149; cyan), metal ions (magenta), 3'-DNA strand (green), and 5'-DNA strand (yellow). This figure was prepared using PyMOL [73].
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