Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

INI Resistance Notes

Last updated on May 29, 2012
Resistance Matrix Resistance Mutation Comments Resistance Mutation Scores Drug Summaries
PositionConsAAComment
51HYH51Y is a nonpolymorphic mutation that is selected in vitro by EVG and in vivo by RAL (Hatano et al. 2010; Reuman et al. 2010). It minimally reduces EVG susceptibility (Jones et al. 2007; Shimura et al. 2007).
54VIV54I is a minimally polymorphic mutation that has been selected in vitro by RAL (Goethals et al. 2010)
66TAT66A is occasionally selected in vivo by RAL usually in combination with other mutations (Charpentier et al. 2008; Hatano et al. 2010). It minimally reduces EVG but not RAL susceptibility (Goethals et al. 2008; Kobayashi et al. 2008).
66TIT66I is a nonpolymorphic mutation selected by EVG (Shimura et al. 2007; Goethals et al. 2008). T66I decreases EVG susceptibility ~15-fold but does not reduce RAL susceptibility (Shimura et al. 2007; Goethals et al. 2008; Kobayashi et al. 2008; Jones et al. 2009; Goethals et al. 2010).
66TKT66K is associated with markedly decreased EVG susceptibility, moderately decreased RAL susceptibility, and possibly decreased 9572 susceptibility(Kobayashi et al. 2008; Seki et al. 2010).
68LVIL68VI are polymorphic accessory INI-resistance mutations selected in vivo by EVG that contribute to decreased RAL and EVG susceptibility in combination with E92Q (Goodman et al. 2008).
72IIV72I is a highly polymorphic mutation selected in vitro by pre-RAL/EVG INIs. It does not decrease susceptibility INI susceptibility (Fransen et al. 2006; Goethals et al. 2008; Low et al. 2009; da Silva et al. 2010).
74LMRL74MR is a polymorphic accessory INI-resistance mutation selected by RAL (Cooper et al. 2008; Sichtig et al. 2009; Wittkop et al. 2009). It does not decrease INI susceptibility alone but decreases RAL susceptibility in combination with N155H (Kobayashi et al. 2008; Miller et al. 2008; Jones et al. 2009; Reuman et al. 2010).
92EQE92Q is a nonpolymorphic mutation selected by RAL and EVG (Shimura et al. 2007; Goethals et al. 2008; Malet et al. 2008; Jones et al. 2009; Sichtig et al. 2009). It reduces RAL and EVG susceptibility by about 5 and >30-fold, respectively(Shimura et al. 2007; Goethals et al. 2008; Jones et al. 2009; Goethals et al. 2010). E92Q emerged during in vitro passage with 9572, but only minimally reduces 9572 susceptibility (Sato et al. 2009; Sato et al. 2010).
92EVE92V has been reported to emerge during in vitro passage with GS-9160 and to reduce RAL and EVG susceptibility 10 and 40-fold, respectively (Jones et al. 2009)
95QKQ95K is a minimally polymorphic accessory INI-resistance mutation selected in vitro by EVG and in vivo by RAL (Shimura et al. 2007; Merck 2009). By itself it has little if any effect on INI susceptibility (Shimura et al. 2007)
97TAT97A is a polymorphic accessory INI-resistance mutation selected by RAL often in combination with Y143 mutations (Malet et al. 2008; Miller et al. 2008; Canducci et al. 2009; Fransen et al. 2009a; Reuman et al. 2010). It has no effect on INI susceptibility alone but markedly reduces RAL susceptibility in combination with Y143CR it markedly reduces(Fransen et al. 2009a; Reuman et al. 2010).
114HYH114Y is a nonpolymorphic accessory resistance mutation selected in vitro by EVG (Goethals et al. 2008).
121FYF121Y is a nonpolymorphic mutation that is selected in vitro by RAL (Rowley 2008) and EVG (Shimura et al. 2007). It reduces susceptibility to RAL and EVG by about 5 and 10-fold, respectively (Jones et al. 2007; Shimura et al. 2007; Kobayashi et al. 2008). It has not been observed in clinical isolates.
125TKT125K is a nonpolymorphic mutation selected in vitro by L870,810. It has not been selected in vivo with current INIs nor found to decrease their susceptibility (Shimura et al. 2007; Kobayashi et al. 2008; Rowley 2008).
128ATA128T is a nonpolymorphic mutation selected in vitro by EVG but which does not reduce INI susceptibility (Fikkert et al. 2004; Goethals et al. 2008)
138EKAE138KA are nonpolymorphic accessory resistance mutations selected in vitro and in vivo by RAL, EVG, and 9572 usually in combination with Q148 mutations(Hazuda et al. 2007; McColl et al. 2007; Sato et al. 2009; Goethals et al. 2010). Alone they do not reduce INI susceptibility but in combination with Q148 mutations they reduce RAL and EVG susceptibility >100-fold and 9572 susceptibility >10-fold (Shimura et al. 2007; Goethals et al. 2008; Jones et al. 2009; Seki et al. 2010).
140GSACG140S is a nonpolymorphic mutation that usually occurs with Q148HRK in patients receiving RAL (Charpentier et al. 2008; Canducci et al. 2009; Sichtig et al. 2009; Wittkop et al. 2009; Hatano et al. 2010) and EVG (McColl et al. 2007). By itself it does not reduce INI susceptibility(Jones et al. 2009; Quercia et al. 2009; Goethals et al. 2010). However, in combination with Q148HRK, it reduces RAL and EVG susceptibility >100-fold and 9572 ~10-fold. G140AC are less well-studied variants that appear to have effects similar to G140S (Jones et al. 2009; Quercia et al. 2009).
143YCRHY143CR are nonpolymorphic mutations selected by RAL (Canducci et al. 2009; Sichtig et al. 2009; Wittkop et al. 2009; Hatano et al. 2010). Alone Y143C and Y143R reduce RAL susceptibility by ~5 and 20-fold respectively but with T97A or other accessory mutations, they reduce RAL susceptibility >100-fold (Fransen et al. 2009a; Reuman et al.). Y143 mutations have no effect on EVG or 9572 susceptibility (DeAnda et al. 2010; Seki et al. 2010). Y143H is a less common mutation at this position that may be primarily transitional.
145PSP145S is a nonpolymorphic mutation that has been selected in vitro by EVG and causes high-level resistance to EVG (Garvey et al. 2008; Kobayashi et al. 2008; Seki et al. 2010).
146QPQ146P is a nonpolymorphic mutation that has been selected in vitro by EVG and shown to reduce EVG susceptibility about 10-fold (Shimura et al. 2007). Its effect on RAL susceptibility is not known.
147SGS147G is a nonpolymorphic mutation selected by EVG (McColl et al. 2007). It reduces EVG susceptibility 5 to 10-fold (Shimura et al. 2007) but has minimal if any effect on RAL susceptibility (Van Baelen et al. 2009).
148QHKRQ148HKR are nonpolymorphic mutations selected by RAL and EVG (McColl et al. 2007; Cooper et al. 2008; Canducci et al. 2009; Sichtig et al. 2009; Wittkop et al. 2009; Hatano et al. 2010). By itself Q148H reduces RAL and EVG susceptibility about 5-10 fold and Q148RK reduce RAL and EVG susceptibility >30-100 fold. With G140S, Q148HRK reduce RAL and EVG susceptibility >100-fold. (Kobayashi et al. 2008; Fransen et al. 2009b; Jones et al. 2009; Goethals et al. 2010). (McColl et al. 2007; Fransen et al. 2009a; Jones et al. 2009). Q148HKR alone have minimal effects on 9572 susceptibility but cause >10-fold decreased susceptibility in combination with E138K +/- G140S (Seki et al. 2010).
151VAV151A has been reported to emerge during INI-selection pressure in vitro and has been associated with ~5-fold reduced susceptibility to RAL and EVG (Jones et al. 2009).
151VIV151I is a polymorphic mutation which has been selected in vitro by multiple INIs but which has no effect on RAL or EVG susceptibility (Hazuda et al. 2004; Markowitz et al. 2007; McColl et al. 2007; Rowley 2008; Low et al. 2009).
151VLV151L has been selected in vitro by early investigational INIs but not in vivo with current INIs. It decreases susceptibility to RAL, EVG, and 9572 (Kobayashi et al. 2008; Seki et al. 2010).
153SYS153Y is a nonpolymorphic accessory mutation that has been selected in vitro by EVG usually with T66I (Jones et al. 2007; Shimura et al. 2007). By itself it minimally decreases EVG and 9572 susceptibility (Jones et al. 2007; Kobayashi et al. 2008; Marinello et al. 2008).
154MILM154IL are polymorphic mutations selected in vitro by pre-RAL/EVG INIs (Hazuda et al. 2000; Hazuda et al. 2004). They do not appear to be selected by nor decrease susceptibility to RAL or EVG (Kobayashi et al. 2008; Low et al. 2009; Miller 2009).
155NHN155H is a nonpolymorphic mutation selected by RAL and EVG (McColl et al. 2007; Cooper et al. 2008; Malet et al. 2008; Canducci et al. 2009; Sichtig et al. 2009; Wittkop et al. 2009; Hatano et al. 2010). It decreases RAL and EVG susceptibility >20-fold (Kobayashi et al. 2008; Jones et al. 2009; Goethals et al. 2010; Reuman et al. 2010). N155H contributes to 9572 resistance in combination with other INI-resistance mutations (Seki et al. 2010).
155NSN155S is an uncommon nonpolymorphic INI-resistance mutation, selected in vitro by L870,810, that decreases RAL and EVG susceptibility to an extent less than that of N155H (Kobayashi et al. 2008; Jones et al. 2009; Goethals et al. 2010).
157EQE157Q is a minimally polymorphic mutation that is selected in vitro by EVG (Jones et al. 2007; Shimura et al. 2007) and rarely in vivo by RAL (Malet et al. 2008). It appears to have minimal if any effect on INI susceptibility (Goethals et al. 2010; Reuman et al. 2010).
163GRKG163RK are polymorphic accessory INI-resistance mutation that usually occur in combination with N155H in patients receiving RAL (Markowitz et al. 2007; Merck 2009). They do not appear to reduce INI susceptibility (Shimura et al. 2007).
193GEG193E emerged in combination with E92Q during in vitro passage with 9572 (Sato et al. 2009). However, it does not decrease 9572 susceptibility.
201VIV201I is a common polymorphism possibly associated with reduced susceptibility to early investigational INIs but not to current INIs (Hombrouck et al. 2008; Low et al. 2009; Miller 2009; da Silva et al. 2010).
203IMI203M is a polymorphic mutation that may occur with increased frequency patients receiving RAL but appears to have no effect on INI susceptibility (Cooper et al. 2008; Malet et al. 2008; da Silva et al. 2010).
206TST206S is a common polymorphism that may occur with increased frequency patients receiving RAL but which does not affect INI susceptibility (Low et al. 2009; Miller 2009; da Silva et al. 2010).
230SNS230N was reported to possibly be associated with reduced susceptibility to the early investigational INIs. However, it does not appear to be selected by or reduce susceptibility to current INIs (Low et al. 2009). S230N is polymorphic.
230SRS230R was reported to possibly be associated with reduced susceptibility to the early investigational INIs. However, it does not appear to be selected by or reduce susceptibility to current INIs (Low et al. 2009). S230R is not polymorphic.
263RKR263K is a nonpolymorphic mutation selected in vitro by EVG and shown to reduce its susceptibility by ~5 fold (Jones et al. 2007)

Relevant references:
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  • da Silva D, Van Wesenbeeck L, Breilh D, Reigadas S, Anies G et al (2010). HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother 65(6): 1262-1269.
  • DeAnda F, Hattori K, Yoshinaga T, Kawasuji T, Underwood M (2010). Structural models of HIV-1 integrase and DNA in complex with S/GSK1349572, raltegravir, and elvitegravir: structure-based rationale for INI resistance profiles [abstract 59]. Antiviral Therapy 15(Suppl 2): A73.
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  • Garvey EP, Johns BA, Gartland MJ, Foster SA, Miller WH et al (2008). The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral. Antimicrob Agents Chemother 52(3): 901-908.
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