Constraints on molecular evolution of HIV-1 drug resistance related genes from protein structure
Objective 
To elucidate constraints on the evolution of HIV drug resistance from protein structure and to analyze the characteristics of HIV drug resistance through a prospective cohort study among 65 HIV infectors receiving high active anti-retroviral therapy (HARRT). 
 
 
Methods 
20 ml of peripheral venous blood sample was collected from each subject every 6 months over a 4 year-follow up since 2003 and added into ethylene-diamine-tetra-acetic acid (EDTA) tube. HIV RNAs were extracted from the blood samples. More than 400 sequences encoding the reverse transcripatase (RT) of HIV were obtained after RT-PCR amplification and sequencing analysis. The sequences were further analyzed for a better understanding of the molecular evolution, drug resistance mutations and 3D protein structure. 
 
 
Results 
Most amino acids sites were conservative in RT protein and only 12.44% of the sites had mutations. Most high level mutations associated with resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs) located at the core of protein, while medium level mutations associated with resistance to NNRTIs located at the surface of protein. Most high level mutations associated with resistance to nucleoside reverse transcriptase inhibitor (NRTIs) located at the surface of protein, while low level mutations associated with resistance to NRTIs located at the core of protein. 
 
 
Conclusion 
Mutations that were associated with drug resistance to NRTIs and NNRTIs were occurred in different parts of HIV RT protein, which would be beneficial for the design and develop of ART drugs targeting RT. 
 
 
Key words: 
HIV-1; Selection pressure; Fitness; Structural constraint