Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density.
Highly active anti-retroviral therapy (HAART) has been very effective in reducing viral loads in human immunodeficiency virus (HIV)-1 patients. However, current therapies carry detrimental side effects, require complex drug regimes and are threatened by the emergence of drug-resistant variants. There is an urgent need for new anti-HIV drugs that target different stages of the replication cycle. Several synthetic small organic molecules that inhibit HIV infection by binding to the CCR5 coreceptor without causing cell activation have already been reported. Here, we have exploited a series of CCR5 antagonists to investigate their effects on diverse HIV and the simian counterpart (SIV) isolates for infection of a variety of cell types via different concentrations of cell surface CCR5. These inhibitors show no cross-reactivity against alternative HIV coreceptors including CCR3, CCR8, GPR1, APJ, CXCR4 and CXCR6. They are able to inhibit a diverse range of R5 and R5X4 HIV-1 isolates as well as HIV-2 and SIV strains. Inhibition was observed in cell lines as well as primary PBMCs and macrophages. The extent of inhibition was dependent on cell type and on cell surface CCR5 concentration. Our results underscore the potential of CCR5 inhibitors for clinical development.
Willey
Samantha
S
Center for AIDS Research, Program in Molecular Medicine, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Biotech II, 373 Plantation St, Worcester, MA 01605, USA.
Peters
Paul J
PJ
Sullivan
W Matthew
WM
Dorr
Patrick
P
Perros
Manos
M
Clapham
Paul R
PR
D000577:Amides / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000187:drug effects; D002460:Cell Line; D018946:Chemokine CCL5 / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D015498:HIV-2 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000821:virology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology / Q000502:physiology*
D000577:Amides; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D018946:Chemokine CCL5; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D011956:Receptors, Cell Surface; C119369:TAK 779