Title

HIV reverse transcriptase: Structural interpretation of drug resistant genetic variants from India

Authors

Abraham J. Kandathil^1,$, Agnel P. Joseph^2,$, R. Kannangai¹, N. Srinivasan², Oriapadicakal C. Abraham³ , Susanne A. Pulimood⁴ and G. Sridharan^1*

Affiliation

¹Departments of Clinical Virology, Christian Medical College, Vellore, India; ²Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India; ³Internal Medicine and ⁴Dermatology, Christian Medical College, Vellore, India; ^$Joint first authors

Email

gopalansridharan@hotmail.com

Article Type

Hypothesis

Date

Received June 05, 2009; Revised June 18, 2009; Accepted July 15, 2009; Published August 20, 2009

Abstract

The reverse transcriptase (RT) enzyme is the prime target of nucleoside/ nucleotide (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors. Here we investigate the structural basis of effects of drug-resistance mutations in clade C RT using three-dimensional structural modeling. Apropos the expectation was for unique mechanisms in clade C based on interactions with amino acids of p66 subunit in RT molecule. 3-D structures of RT with mutations found in sequences from 2 treatment naïve, 8 failed and one reference clade C have been modeled and analyzed. Models were generated by computational mutation of available crystal structures of drug bound homologous RT. Energy minimization of the models and the structural analyses were carried out using standard methods. Mutations at positions 75,101,118,190,230,238 and 318 known to confer drug resistance were investigated. Different mutations produced different effects such as alteration of geometry of the drugbinding pocket, structural changes at the site of entry of the drug (into the active site), repositioning the template bases or by discriminating the inhibitors from their natural substrates. For the mutations analyzed, NRTI resistance was mediated mainly by the ability to discriminate between inhibitors and natural substrate, whereas, NNRTI resistance affected either the drug entry or the geometry of the active site. Our analysis suggests that different mutations result in different structural effects affecting the ability of a given drug to bind to the RT. Our studies will help in the development of newer drugs taking into account the presence of these mutations and the structural basis of drug resistance.

Keywords

Drug resistance, Genetic mutations, HIV-1, Reverse transcriptase, Structural modeling

Citation

Kandathil et al., Bioinformation 4(1): 36-45 (2009)

Edited by

P. Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.