We are investigating the role of mutations in the HIV reverse transcriptase that are highly prevalent in viral isolates from drug-treated individuals on drug resistance and virological failure. This includes silent mutations (that do not code for amino acid changes) selected during drug treatment.

Our studies have led to the identification of N348I in the HIV reverse transcriptase connection domain that is prevalent in drug-treated individuals and leads to dual reverse transcriptase inhibitor class resistance.

Outcomes

Tachedjian G and Sluis-Cremer N. Chapter 13. Role of RNase H activity in NRTI/NNRTI Drug Resistance. pp281 – 303. Edited by Stuart LeGrice and Mattias Gotte. In Human Immunodeficiency virus reverse transcriptase: A bench-to-bedside success. Springer Publishing Company, New York. Published August 2013. ISBN 978-1-4614-7290-2

Publications

2016

• Increasing Prevalence of Synonymous Mutations K65K and K66K in HIV-1 subtype B reverse transcriptase.
  Telwatte S, Brumme CJ, Hearps AC, Latham CF, Hayward JA, Sonza S, Sluis-Cremer N, Harrigan PR, Tachedjian G
  AIDS. 2016 Sep; 30(18):2787-2793
• High fidelity simian immunodeficiency virus reverse transcriptase mutants have impaired replication in vitro and in vivo.
  Lloyd SB, Lichtfuss M, Amarasena TH, Alcantara S, De Rose R, Tachedjian G, Alinejad-Rokny H, Venturi V, Davenport MP, Winnall WR, Kent SJ
  Virology. 2016 Feb; 492:1-10

2015

• Silent mutations at codons 65 and 66 in reverse transcriptase alleviate indel formation and restore fitness in subtype B HIV-1 containing D67N and K70R drug resistance mutations.
  Telwatte S, Hearps AC, Johnson A, Latham CF, Moore K, Agius P, Tachedjian M, Sonza S, Sluis-Cremer N, Harrigan PR, Tachedjian G
  Nucleic Acids Res. 2015 Mar; Epub ahead of print

2012

• N348I in HIV-1 Reverse Transcriptase Counteracts the Synergy Between Zidovudine and Nevirapine.
  Yap SH, Herman BD, Radzio J, Sluis-Cremer N, Tachedjian G
  J Acquir Immune Defic Syndr. 2012 Jun; 61(12):153-157

2010

• N348I in reverse transcriptase provides a genetic pathway for HIV-1 to select thymidine analogue mutations and mutations antagonistic to thymidine analogue mutations.
  Radzio J, Yap SH, Tachedjian G, Sluis-Cremer N
  AIDS. 2010 Mar; 24(5):659-667
• N348I in HIV-1 reverse transcriptase decreases susceptibility to tenofovir and etravirine in combination with other resistance mutations.
  Sluis-Cremer N, Moore K, Radzio J, Sonza S, Tachedjian G
  AIDS. 2010 Jan; 24(2):317-319

2009

• The human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor resistance mutation I132M confers hypersensitivity to nucleoside analogs.
  Ambrose Z, Herman BD, Sheen CW, Zelina S, Moore KL, Tachedjian G, Nissley DV, Sluis-Cremer N
  J Virol. 2009 Apr; 83(8):3826-3833

2007

• N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance.
  Yap SH, Sheen CW, Fahey J, Zanin M, Tyssen D, Lima VD, Wynhoven B, Kuiper M, Sluis-Cremer N, Harrigan PR, Tachedjian G
  PLoS Med. 2007 Dec; 4(12):e335