Adaptation to blockade of human immunodeficiency virus type 1 entry imposed by the anti-CCR5 monoclonal antibody 2D7.
The second extracellular loop (ECL2) domain of CC-chemokine receptor 5 (CCR5) has been proposed as a specific target site for therapeutic agents aimed at blocking CCR5-dependent entry by human immunodeficiency virus type I (HIV-1). We have adapted two CCR5-using HIV-1 isolates, prototypic JR-CSF, and a primary isolate, 11-121, to replicate in vitro in the presence of high concentrations of a monoclonal antibody (MAb 2D7) specific for the CCR5 ECL2 domain. The 75% inhibitory concentrations (IC(75)) for the two 2D7-adapted isolates were approximately 100-fold higher than those for corresponding control isolates passaged without the MAb. Adapted isolates did not acquire the ability to use CXCR4, CCR3, or CCR1. Env clones derived from MAb 2D7-adapted JR-CSF showed several gp120 mutations that were not found in any of the control JR-CSF clones. The in vitro observations suggest that CCR5-using HIV-1 strains might also be able to adapt in vivo to evade an ECL2-blocking therapeutic agent.
Aarons
E J
EJ
Department of Medicine, Division of Infectious Disease, University of Texas Southwestern Medical Center, Texas, Dallas 75390, USA.
Beddows
S
S
Willingham
T
T
Wu
L
L
Koup
R A
RA
D000220:Adaptation, Biological / Q000235:genetics*; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D016346:Gene Products, vif / Q000235:genetics; D016336:Gene Products, vpr / Q000235:genetics; D005814:Genes, Viral / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000276:immunology*; D017386:Sequence Homology, Amino Acid; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics; D054320:vif Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000086082:Viroporin Proteins
D000911:Antibodies, Monoclonal; D016346:Gene Products, vif; D016336:Gene Products, vpr; D015699:HIV Envelope Protein gp120; D054298:Human Immunodeficiency Virus Proteins; D019713:Receptors, CCR5; D054334:Viral Regulatory and Accessory Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins