Title: Molecular Mechanisms of Resistance to Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase
Volume: 2
Issue: 2
Author(s): Luis Menendez-Arias, Tania Matamoros, Jerome Deval and Bruno Canard
Affiliation:
Keywords:
hiv, antiviral therapy, nucleosides, reverse transcriptase, resistance, aids
Abstract: Current treatments for human immunodeficiency virus (HIV) infection target viral enzymes such as the protease and the reverse transcriptase (RT), as well as the envelope glycoprotein gp41. RT inhibitors include nucleoside and nonnucleoside inhibitors that bind to distinct sites within the polymerase. Zidovudine, stavudine, zalcitabine, didanosine, lamivudine, abacavir, tenofovir and emtricitabine are converted to active triphosphate analogues and incorporated into the nascent viral DNA in reactions catalyzed by HIV RT. Since nucleoside analogues lack the 3-OH group required for the phosphodiester bond formation, they act as chain terminators of DNA synthesis. Development of drug resistance is a major hurdle towards their long-term efficacy. Mutations in the pol gene selected during treatment with nucleoside analogues confer resistance through different mechanisms: (i) altering discrimination between nucleoside RT inhibitors and natural substrates (dNTPs), or (ii) increasing the RTs phosphorolytic activity, which in the presence of ATP and other pyrophosphate donors allows the removal of chain-terminating nucleotides from the 3 end of the primer. These mechanisms are also relevant for multidrug resistance, as shown for the Q151M complex, or RTs having thymidine analogue resistance mutations and/or insertions at codons 69-70 of the fingers subdomain.
