Effect of the L74I Polymorphism on Fitness of Cabotegravir-Resistant Variants of Human Immunodeficiency Virus 1 Subtype A6

J Infect Dis. 2023 Nov 11;228(10):1352-1356. doi: 10.1093/infdis/jiad291.

Abstract

The presence of human immunodeficiency virus (HIV) 1 subtype A6, characterized by the L74I integrase (IN) polymorphism, is associated with confirmed virologic failure in clinical trials of long-acting cabotegravir and rilpivirine. We investigated the effect of L74I on replication capacity (RC) of recombinant viruses carrying this polymorphism in combination with various IN stand-transfer inhibitor resistance mutations. The presence of L74I conferred greater RC to recombinant viruses expressing HIV-1 A6 IN when present together with G118R, G140R, Q148H, and R263K; no significant difference in RC was observed for the Q148K or R mutants. These findings may explain, in part, the association of HIV-1 subtype A6 with virologic failure.

Keywords: HIV drug resistance; cabotegravir; integrase strand-transfer inhibitors; viral fitness; viral replication capacity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Drug Resistance, Viral / genetics
  • HIV Infections* / drug therapy
  • HIV Integrase Inhibitors* / pharmacology
  • HIV Integrase Inhibitors* / therapeutic use
  • HIV Integrase* / genetics
  • HIV-1* / genetics
  • Humans
  • Mutation
  • Oxazines / therapeutic use
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Virus Replication / genetics

Substances

  • cabotegravir
  • Oxazines
  • HIV Integrase Inhibitors
  • Pyridones
  • HIV Integrase