Skip to content


  • Poster presentation
  • Open Access

Biochemical mechanism of clinical resistance to rilpivirine

  • 1, 2,
  • 1, 2,
  • 3Email author,
  • 1, 2,
  • 1, 2,
  • 1,
  • 1,
  • 1,
  • 4,
  • 4, 5,
  • 1 and
  • 1, 2, 6
BMC Infectious Diseases201212 (Suppl 1) :P94

  • Published:


  • Tenofovir
  • Biochemical Mechanism
  • Virological Failure
  • Drug Susceptibility
  • Nucleoside Reverse Transcriptase Inhibitor


The introduction of HAART has significantly prolonged the life span of HIV-infected patients. However, the error-prone nature of HIV-1 reverse transcriptase (HIV-1 RT) results in the emergence of drug-resistant viruses and threatens the effectiveness of HAART. HIV-1 RT is a primary target of two classes of drugs: nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Recent phase III clinical trials have shown that two HIV-1 RT mutations, E138K and M184I, were the most frequent mutations found in patients that experienced virological failure during therapy that included rilpivirine (RPV), emtricitabine (FTC), and tenofovir (TDF).


To investigate the mechanistic basis for resistance caused by the E138K and M184I mutations we used transient kinetics to characterize the enzymatic properties and drug susceptibility of RTs with these mutations and determined the biochemical mechanism of resistance to RPV. Specifically, we compared wild-type (WT) RT to RTs mutated in one or both of the enzymatic subunits: p66M184I/p51M184I, p66E138K/p51E138K, p66E138K/p51M184I, p66E138K/p51WT, p66WT/p51138K.


Our results show that M184I reduces the catalytic efficiency of RT by more than two-fold (p66M184I/p51M184Ihas more than 2-fold reduced kpol/Kd.dNTP with respect to WT). This defect is compensated by mutation E138K either in both subunits or only in p51 subunit (p66WT/p51138K).


None of the mutations affected the template-primer binding affinity of RT. As expected, M184I does not reduce the susceptibility to RPV. Instead, RPV resistance is achieved by reduction in the binding affinity of the drug to RT because of the E138K mutation in the p51 subunit.

Authors’ Affiliations

Christopher Bond Life Sciences Center, USA
Department of Molecular Microbiology & Immunology, University of Missouri, School of Medicine, Columbia, MO, USA
Department of Biochemistry, University of Allahabad, Allahabad, India
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Canada
McGill University, Montreal, Quebec, Canada
Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA


© Singh et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.