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Characterization of novel non-nucleoside reverse transcriptase (RT) inhibitor resistance mutations at residues 132 and 135 in the 51 kDa subunit of HIV-1 RT

  1. Author:
    Nissley, D. V.
    Radzio, J.
    Ambrose, Z.
    Sheen, C. W.
    Hamamouch, N.
    Moore, K. L.
    Tachedjian, G.
    Sluis-Cremer, N.

  2. Author Address

    Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. NCI Frederick, Gene Regulat & Chromosome Biol Lab, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. Natl Canc Inst, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. Macfarlane Burnet Inst Med Res & Publ Hlth, Mol Interact Grp, Melbourne, Vic 3004, Australia. Monash Univ, Dept Microbiol, Melbourne, Vic 3168, Australia.;Sluis-Cremer, N, Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA.;cremern@dom.pitt.edu
    1. Year: 2007
    2. Date: May
  2. Journal: Biochemical Journal
    1. 404
    2. Pages: 151-157
  4. Type of Article: Article
  5. ISSN: 0264-6021
  1. Abstract:

    Several rare and novel NNRTI [non-nucleoside reverse transcriptase (RT) inhibitor] resistance mutations were recently detected at codons 132 and 135 in RTs from clinical isolates using the yeast-based chimaeric TyHRT (Ty1/HIV-1 RT) phenotypic assay. Ile(132) and Ile(135) form part of the beta 7-beta 8 loop of HIV-1 RT (residues 132-140). To elucidate the contribution of these residues in RT structure-function and drug resistance, we constructed twelve recombinant enzymes harbouring mutations at codons 132 and 135-140. Several of the mutant enzymes exhibited reduced DNA polymerase activities. Using the yeast two-hybrid assay for HIV-1 RT dimerization we show that in some instances this decrease in enzyme activity could be attributed to the mutations, in the context of the 5 1 kDa subunit of HIV-1 RT, disrupting the subunit-subunit interactions of the enzyme. Drug resistance analyses using purified RT, the TyHRT assay and antiviral assays demonstrated that the I132M mutation conferred high-level resistance (> 10-fold) to nevirapine and delavirdine and low-level resistance (similar to 2-3-fold) to efavirenz. The I135A and I135M mutations also conferred low level NNRTI resistance (similar to 2-fold). Subunit selective mutagenesis studies again demonstrated that resistance was conferred via the p51 subunit of HIV-1RT. Taken together, our results highlight a specific role of residues 132 and 135 in NNRTI resistance and a general role for residues in the beta 7-beta 8 loop in the stability of HIV-1RT.

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  2. DOI: 10.1042/bj20061814
  3. View record in Web of Science®
  4. WOS: 000246547300017

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