An anti-CCR5 monoclonal antibody and small molecule CCR5 antagonists synergize by inhibiting different stages of human immunodeficiency virus type 1 entry.
HIV-1 coreceptors are attractive targets for novel antivirals. Here, inhibition of entry by two classes of CCR5 antagonists was investigated. We confirmed previous findings that HIV-1 isolates vary greatly in their sensitivity to small molecule inhibitors of CCR5-mediated entry, SCH-C and TAK-779. In contrast, an anti-CCR5 monoclonal antibody (PA14) similarly inhibited entry of diverse viral isolates. Sensitivity to small molecules was V3 loop-dependent and inversely proportional to the level of gp120 binding to CCR5. Moreover, combinations of the MAb and small molecules were highly synergistic in blocking HIV-1 entry, suggesting different mechanisms of action. This was confirmed by time course of inhibition experiments wherein the PA14 MAb and small molecules were shown to inhibit temporally distinct stages of CCR5 usage. We propose that small molecules inhibit V3 binding to the second extracellular loop of CCR5, whereas PA14 preferentially inhibits subsequent events such as CCR5 recruitment into the fusion complex or conformational changes in the gp120-CCR5 complex that trigger fusion. Importantly, our findings suggest that combinations of CCR5 inhibitors with different mechanisms of action will be central to controlling HIV-1 infection and slowing the emergence of resistant strains.
Safarian
Diana
D
Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Carnec
Xavier
X
Tsamis
Fotini
F
Kajumo
Francis
F
Dragic
Tatjana
T
D000577:Amides / Q000008:administration & dosage; D019380:Anti-HIV Agents / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D065100:CCR5 Receptor Antagonists; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D004357:Drug Synergism; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000502:physiology; D015658:HIV Infections / Q000628:therapy / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D010091:Oximes; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D019713:Receptors, CCR5 / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D000577:Amides; D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D003497:Cyclic N-Oxides; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010091:Oximes; D010446:Peptide Fragments; D010880:Piperidines; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D011994:Recombinant Proteins; C438583:Ancriviroc; C119369:TAK 779