In vivo evolution of X4 human immunodeficiency virus type 1 variants in the natural course of infection coincides with decreasing sensitivity to CXCR4 antagonists.
CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) variants evolve from CCR5-restricted (R5) HIV-1 variants. Early after their first appearance in vivo, X4 HIV-1 variants additionally use CCR5. The ability to use CCR5 in addition to CXCR4 is generally lost late in infection. Here we studied whether this evolution of the coreceptor repertoire is also reflected in a changing sensitivity of X4 variants to CXCR4 antagonists such as peptide T22 and the synthetic compound AMD3100. We observed differences in the concentrations of CXCR4 antagonists needed to suppress replication of X4 HIV variants from different patients. In general, late X4 HIV variants were less sensitive to AMD3100 than were early R5X4 HIV variants. The differences between early R5X4 HIV variants and late X4 variants were less pronounced for T22-mediated inhibition. These results suggest an ongoing evolution of X4 virus variants toward more efficient usage of the cellular entry complex.
Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, The Netherlands.
Evelien H B
EH
Stalmeijer
Ronald P
RP
Van Rij
Brigitte
B
Boeser-Nunnink
Janny A
JA
Visser
Marloes A
MA
Naarding
Dominique
D
Schols
Hanneke
H
Schuitemaker
D019380:Anti-HIV Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001596:Benzylamines; D002460:Cell Line; D000080027:Cyclams; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D023181:Antimicrobial Cationic Peptides; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C076963:T22 protein, synthetic; C088327:plerixafor