Prevalence of genotypic HIV-1 drug resistance in Thailand, 2002

BACKGROUND: The prices of reverse transcriptase (RT) inhibitors in Thailand have been reduced since December 1, 2001. It is expected that reduction in the price of these inhibitors may influence the drug resistance mutation pattern of HIV-1 among infected people. This study reports the frequency of HIV-1 genetic mutation associated with drug resistance in antiretroviral-treated patients from Thailand. METHODS: Genotypic resistance testing was performed on samples collected in 2002 from 88 HIV-1 infected individuals. Automated DNA sequencing was used to genotype the HIV-1 polymerase gene isolated from patients' plasma. RESULTS: Resistance to protease inhibitors, nucleoside and non-nucleoside reverse transcriptase inhibitors were found in 10 (12%), 42 (48%) and 19 (21%) patients, respectively. The most common drug resistance mutations in the protease gene were at codon 82 (8%), 90 (7%) and 54 (6%), whereas resistant mutations at codon 215 (45%), 67 (40%), 41 (38%) and 184 (27%) were commonly found in the RT gene. This finding indicates that genotypic resistance to nucleoside reverse transcriptase inhibitors was prevalent in 2002. The frequency of resistant mutations corresponding to non-nucleoside reverse transcriptase inhibitors was three times higher-, while resistant mutation corresponding to protease inhibitors was two times lower than those frequencies determined in 2001. CONCLUSION: This study shows that the frequencies of RT inhibitor resistance mutations have been increased after the reduction in the price of RT inhibitors since December 2001. We believe that this was an important factor that influenced the mutation patterns of HIV-1 protease and RT genes in Thailand

Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides

Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding “pseudoenergies”, we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 µM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery

Identifying Inhibitors of the SARS Coronavirus Proteinase

Abstract—The Severe Acute Respiratory Syndrome (SARS) is a serious respiratory illness that has recently been reported in parts of Asia and Canada. In this study, we use molecular dynamics (MD) simulations and docking techniques to screen 29 approved and experimental drugs against the theoretical model of the SARS CoV proteinase as well as the experimental structure of the transmissible gastroenteritis virus (TGEV) proteinase. Our predictions indicate that existing HIV-1 protease inhibitors, l-700,417 for instance, have high binding affinities and may provide good starting points for designing SARS CoV proteinase inhibitors. # 2003 Elsevier Ltd. All rights reserved. A novel coronavirus (CoV) has been isolated and identified as the cause of the severe acute respiratory syndrome (SARS), 1 for which there is currently no effective treatment. The SARS CoV genome sequence has been recently published. 2 The structure of the main proteinase, essential for SARS CoV replication, can be deduced from its similarity (43 % sequence identity) to the X-ray crystallography structure of the proteinase from the porcine transmissible gastroenteritis virus (TGEV), als