Resistance to novel drug classes.
OBJECTIVE
Understanding the mechanisms that underlie resistance development to novel drugs is essential to a better clinical management of resistant viruses and to prevent further resistance development and spread.


RESULTS
Integrase inhibitors and CCR5 antagonists are the more recent antiretroviral classes developed. The HIV-1 integrase, responsible for the chromosomal integration of the newly synthesized double-stranded viral DNA into the host genomic DNA, represents a new and important target; and two integrase inhibitors (INIs), raltegravir and elvitegravir, have been shown promising results in clinical trials. Viral entry is also an attractive step for the development of new drugs against HIV variants resistant to current antiretroviral drugs, and two CCR5 antagonists have been designed to inhibit HIV-1 binding to R5 co-receptor and are under clinical investigation.


CONCLUSIONS
Drug resistance to INIs occurs through the selection of mutations within HIV integrase. The kinetic of selection seems rapid and one mutation alone is able to confer resistance to integrase inhibitor, suggesting that this class of drug has a low genetic barrier. Two ways could explain the failure of the CCR5 antagonist class: a rapid outgrowth of pre-existing archived X4 virus or the selection of a resistance to CCR5 antagonists through amino acid changes in V3 loop.
Marcelin
Anne-Genevieve
AG
UMR INSERM UPMC, Université Pierre et Marie Curie U 943, AP-HP, Hôpital Pitié Salpêtrière, Laboratoire de Virologie, Paris, France.
Ceccherini-Silberstein
Francesca
F
Perno
Carlo-Federico
CF
Calvez
Vincent
V
D044966:Anti-Retroviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans
D044966:Anti-Retroviral Agents; D065100:CCR5 Receptor Antagonists; D019428:HIV Integrase Inhibitors