Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors.
Integration of viral DNA into the host chromosome is an essential step in the life cycle of retroviruses and is facilitated by the viral integrase enzyme. The first generation of integrase inhibitors recently approved or currently in late-stage clinical trials shows great promise for the treatment of human immunodeficiency virus (HIV) infection, but virus is expected to develop resistance to these drugs. Therefore, we used a novel resistance selection protocol to follow the emergence of resistant HIV in the presence of the integrase inhibitor elvitegravir (GS-9137). We find the primary resistance-conferring mutations to be Q148R, E92Q, and T66I and demonstrate that they confer a reduction in susceptibility not only to elvitegravir but also to raltegravir (MK-0518) and other integrase inhibitors. The locations of the mutations are highlighted in the catalytic sites of integrase, and we correlate the mutations with expected drug-protein contacts. In addition, mutations that do not confer reduced susceptibility when present alone (H114Y, L74M, R20K, A128T, E138K, and S230R) are also discussed in relation to their position in the catalytic core domain and their proximity to known structural features of integrase. These data broaden the understanding of antiviral resistance against integrase inhibitors and may give insight facilitating the discovery of second-generation compounds.
Goethals
Olivia
O
Tibotec BVBA, Mechelen, Belgium. rclayton@its.jnj.com
Clayton
Reginald
R
Van Ginderen
Marcia
M
Vereycken
Inge
I
Wagemans
Elisabeth
E
Geluykens
Peggy
P
Dockx
Koen
K
Strijbos
Rudy
R
Smits
Veerle
V
Vos
Ann
A
Meersseman
Geert
G
Jochmans
Dirk
D
Vermeire
Kurt
K
Schols
Dominique
D
Hallenberger
Sabine
S
Hertogs
Kurt
K
D020134:Catalytic Domain; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D019429:Integrase Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D020125:Mutation, Missense; D015363:Quinolones / Q000494:pharmacology*
D019429:Integrase Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1