Dichotomous mechanisms of HIV-1 escape from the CCR5 inhibitor

maraviroc by resistant virus generated in vitro and primary viruses with reduced

baseline sensitivity

Michael Roche, Jasminka Sterjovski, Anne Ellett, Martin R. Jakobsen, Lachlan Gray, Mike Westby, Becky Jubb, Anthony L. Cunningham, Melissa Churchill, and Paul R. Gorry

Burnet Institute

MVC Resistant Virus has increased reliance on the N-terminus of CCR5

• MVC is a CCR5 antagonist and inhibits HIV-1 ENV binding to CCR5 via an allosteric mechanism

• HIV becomes resistant in vitro by continued use of CCR5 – binding to the inhibitor/CCR5 complex

• Characterized by plateau in maximal inhibition, not changes in IC50

MVC Resistance associated with• “Plateau” in Maximal Percent Inhibition (MPI)• Increased reliance on the N-terminus of CCR5 which is more

pronounced in the presence of drug - also seen with other CCR5 antagonists AD1011, Aplaviroc2 and Vicriviroc3

• Reduced replication kinetics in macrophages (suggesting a less efficient CCR5 interaction

SENS RES RES + MVC

1. Berro, 2009 PLOS Pathogens 2. Pfaff, 2010 J Virol 3. Ogert, 2009 J Virol

- C

- N

Primary HIV-1 R5 viruses with reduced baseline MVC sensitivity have reduced reliance on the CCR5 N-terminus

• Do viruses with a reduced baseline sensitivity have a similar mechanism of action?

Reduced baseline sensitivity to MVC associated with

• Reduced reliance on residues in the N-terminus of CCR5 (Y15) but increased reliance on residues in ECL2 (H181)

• Increased entry into macrophages (suggesting a more efficient CCR5 interaction5)

Y15AN-terminus

H181AECL2

4. Gray, 2005 Virology5. Sterjovski, 2010 Virology

Dichotomous mechanisms of HIV-1 escape from MVC inhibition

- C

- N

N-terminus ECL2

Non-competitive escape MVC Resistance CCR5 efficiency

Macrophage Tropism

Competitive escape MVC Sensitivity CCR5 efficiency Macrophage Tropism

CCR5