Genetic barriers for integrase inhibitor drug resistance in HIV type-1 B and CRF02_AG subtypes

Abstract

Background: HIV type-1 (HIV-1) integrase (IN) inhibitor resistance is the consequence of mutations that are selected in the viral IN gene targeted by antiretroviral drugs, such as raltegravir (RAL) and elvitegravir (EVG). The genetic barrier, defined as the number of viral mutations required to overcome the drug-selective pressure, is one of the important factors in the development of drug resistance. The genetic barrier for IN inhibitor resistance was compared between HIV-1 subtype B and HIV-1 subtype CRF02_AG, which is highly prevalent in West Africa and becoming more frequent in developed countries.

Methods: IN nucleotide sequences from 73 HIV-1 subtype B and 77 HIV-1 subtype CRF02_AG antiretroviral-naive patients were examined at 19 IN amino acid positions implicated in RAL and EVG resistance.

Results: The majority (14/19) of the studied positions showed a high degree of conservation of the predominant codon sequences leading to a similar genetic barrier between subtypes B and CRF02_AG. Nevertheless, at positions 140 and 151, the variability between subtypes affected the genetic barrier for the mutations G140C, G140S and V1511 with a higher genetic barrier being calculated for subtype CRF02_AG.

Conclusions: The major IN mutations E92Q, Q148K/R/H, N155H and E157Q (implicated in the resistance of IN inhibitors RAL and EVG) are highly conserved between subtypes B and CRF02_AG and display a similar genetic barrier. However, subtype CRFO2_AG showed a higher genetic barrier to acquire mutations 6140S, 6140C and V1511 as compared with subtype B, which could play a role in the resistance to RAL and/or EV6.