TY - JOUR
T1 - Resistance of Human Immunodeficiency Virus Type 1 to a Third-Generation Fusion Inhibitor Requires Multiple Mutations in gp41 and Is Accompanied by a Dramatic Loss of gp41 Function
AU - Eggink, Dirk
AU - Bontjer, Ilja
AU - Langedijk, Johannes P. M.
AU - Berkhout, Ben
AU - Sanders, Rogier W.
PY - 2011
Y1 - 2011
N2 - HIV-1 entry into target cells requires the fusion of viral and cellular membranes. This process is an attractive target for therapeutic intervention, and a first-generation fusion inhibitor, T20 (Enfuvirtide; Fuzeon), was approved for clinical use in 2003. Second-generation (T1249) and third-generation (T2635) fusion inhibitors with improved stability and potency were developed. Resistance to T20 and T1249 usually requires one or two amino acid changes within the binding site. We studied the in vitro evolution of resistance against T2635. After 6 months of culturing, a multitude of resistance mutations was identified in all gp41 subdomains, but no single mutation provided meaningful T2635 resistance. In contrast, multiple mutations within gp41 were required for resistance, and this was accompanied by a dramatic loss of viral infectivity. Because most of the escape mutations were situated outside the T2635 binding site, a decrease in drug target affinity cannot account for most of the resistance. T2635 resistance is likely to depend on altered kinetics of six-helix bundle formation, thus limiting the time window for T2635 to interfere with membrane fusion. Interestingly, the loss of virus infectivity caused by T2635 resistance mutations in gp41 was partially compensated for by a mutation at the base of the V3 domain in gp120. Thus, escape from the third-generation HIV-1 fusion inhibitor T2635 is mechanistically distinct from resistance against its predecessors T20 and T1249. It requires the accumulation of multiple mutations in gp41, is accompanied with a dramatic loss of gp41 function, and induces compensatory mutations in gp120
AB - HIV-1 entry into target cells requires the fusion of viral and cellular membranes. This process is an attractive target for therapeutic intervention, and a first-generation fusion inhibitor, T20 (Enfuvirtide; Fuzeon), was approved for clinical use in 2003. Second-generation (T1249) and third-generation (T2635) fusion inhibitors with improved stability and potency were developed. Resistance to T20 and T1249 usually requires one or two amino acid changes within the binding site. We studied the in vitro evolution of resistance against T2635. After 6 months of culturing, a multitude of resistance mutations was identified in all gp41 subdomains, but no single mutation provided meaningful T2635 resistance. In contrast, multiple mutations within gp41 were required for resistance, and this was accompanied by a dramatic loss of viral infectivity. Because most of the escape mutations were situated outside the T2635 binding site, a decrease in drug target affinity cannot account for most of the resistance. T2635 resistance is likely to depend on altered kinetics of six-helix bundle formation, thus limiting the time window for T2635 to interfere with membrane fusion. Interestingly, the loss of virus infectivity caused by T2635 resistance mutations in gp41 was partially compensated for by a mutation at the base of the V3 domain in gp120. Thus, escape from the third-generation HIV-1 fusion inhibitor T2635 is mechanistically distinct from resistance against its predecessors T20 and T1249. It requires the accumulation of multiple mutations in gp41, is accompanied with a dramatic loss of gp41 function, and induces compensatory mutations in gp120
U2 - https://doi.org/10.1128/JVI.05331-11
DO - https://doi.org/10.1128/JVI.05331-11
M3 - Article
C2 - 21835789
SN - 0022-538X
VL - 85
SP - 10785
EP - 10797
JO - Journal of Virology
JF - Journal of Virology
IS - 20
ER -