HIV-1 escape from the CCR5 antagonist maraviroc associated with an altered and less

efficient mechanism of gp-120 CCR5 engagement that attenuates macrophage tropism

Michael RochePhD StudentBurnet Institute

HIV Resistance to Maraviroc• HIV uses CD4 as the primary receptor and either CCR5 or CXCR4 as a

coreceptor for entry• Maraviroc (MVC) is the first approved drug in a new class of entry

inhibitors – CCR5 antagonists• Bind and lock CCR5 in a conformation not recognized by HIV Env –

allosteric inhibition• HIV can become resistant to MVC by emergence pre-existing CXCR4 using

variants or by using the MVC modified form of CCR5• Characterized by plateaus in inhibition (MPI) – non-competitive resistance• Is there an infectivity cost associated with using the MVC modified form of

CCR5, such as changes in cell tropism?

Competitive Resistance Non-competitive Resistance

MVC attenuates Macrophage tropism of MVC resistant Env

• MVC resistant Env from isolate generated in vitro• Characteristic resistant phenotype• High plateau – low level of resistance• Associated with a less efficient gp120-CCR5 interaction• Does this alter the cell tropism of the resistant virus?• MVC attenuates macrophage but not PBMC infection• Infectivity cost associated with resistance for this in vitro generated virus

Level of MVC resistance in vivo is associated with the level of attenuation of Macrophage tropism by MVC

• Envs cloned from 2 patients who failed MVC therapy with CCR5-using virus• Patient 17 displays high plateau, thus ‘very weak’ resistance• Patient 24 displays lowered plateau, thus ‘strong’ resistance• Level of resistance associates with attenuation of macrophage infection by MVC

Patient 17‘Very Weak’ Resistance

Patient 24‘Strong’ Resistance

Conclusion: Maintaining MVC despite the development of resistance (in some cases) may spare the macrophage reservoir from infection and thus may have some clinical benefit

Acknowledgments

Gorry LabPaul GorryMelissa ChurchillJasminka SterjovskiAnne EllettMiranda MooreHamid SalimiseyedabadMartin JakobsenKieran CashinLachlan GrayDaniel Cowley

Paul RamslandSharon Lewin

Pfizer LtdMike WestbyBecky Jubb

UCLABenhur LeeFillipo Posta