HIV drug resistance against strand transfer integrase inhibitors

Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell’s chromatin. Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance. Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second-generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants. In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual. This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold-changes in resistance of resistant variants in in vitro assays. While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the “second-generation” drugs of this class. This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development.

• Publication year

  2017

• Venue

  Retrovirology

• Publication date

  2017-06-05

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s12977-017-0360-7PMID 28583191PMCID 5460515
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2017cited by this paper
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  2016cited by this paper
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  2016cited by this paper
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  2016cited by this paper
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  2016cited by this paper
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  2014cited by this paper
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  2012cited by this paper
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  2012influential reference
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  2012cited by this paper
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  2012cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2008cited by this paper
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  2008cited by this paper
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  2008cited by this paper
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