Cell surface expression of CCR5 and other host factors influence the inhibition of HIV-1 infection of human lymphocytes by CCR5 ligands.
Several CCR5 ligands, including small molecules and monoclonal antibodies (MAbs), are being developed as therapies for infection with strains of human immunodeficiency virus type 1 (HIV-1) that use CCR5 for entry (R5 viruses). The efficacy of such therapies could be influenced by inter-individual differences in host factors, such as CCR5 expression levels. To study this, we used peripheral blood mononuclear cells (PBMCs) from humans and rhesus macaques. The half-maximal inhibitory concentrations (IC(50)) of the small-molecule CCR5 ligands CMPD167, UK427,857 and SCH-D, and of the PRO 140 MAb, differ by >2 logs in a donor-dependent manner. We studied this variation by using flow cytometry to measure CCR5 expression on PBMCs from six of the human donors: the IC(50) values of both SCH-D and PRO 140 correlated with CCR5 expression (R(2)=0.64 and 0.99, respectively). We also determined the efficacy of the CCR5 ligands against HIV-1 infection of HeLa-derived cell lines that express CD4 at the same level but vary 2-fold in CCR5 expression (JC.48 and JC.53 cells). The moderately greater CCR5 expression on the JC.53 than the JC.48 cells was associated with proportionately higher median IC(50) values for all four CCR5 ligands but not for a soluble CD4-based inhibitor or a non-nucleoside reverse transcriptase inhibitor. We conclude that differences in CCR5 expression on human PBMCs, which can be affected by CCL3L1 gene dose, may influence the antiviral potency of CCR5 ligands in vitro, but other host factors are also likely to be involved. These host factors may affect the clinical activity of CCR5 inhibitors, including their use as topical microbicides to prevent HIV-1 transmission.
Ketas
Thomas J
TJ
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Kuhmann
Shawn E
SE
Palmer
Ashley
A
Zurita
Juan
J
He
Weijing
W
Ahuja
Sunil K
SK
Klasse
Per Johan
PJ
Moore
John P
JP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics; D003510:Cyclohexanes / Q000378:metabolism / Q000494:pharmacology; D018628:Gene Dosage; D015497:HIV-1 / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D008253:Macaca mulatta; D000077592:Maraviroc; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D000911:Antibodies, Monoclonal; C492767:CCL3L1 protein, human; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; C480490:CMPD 167; D019742:Chemokines, CC; D003510:Cyclohexanes; D008024:Ligands; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D019713:Receptors, CCR5; D014230:Triazoles; D014633:Valine; D000077592:Maraviroc; C486781:vicriviroc