Highly potent RANTES analogues either prevent CCR5-using human immunodeficiency virus type 1 infection in vivo or rapidly select for CXCR4-using variants.
The natural ligands for the CCR5 chemokine receptor, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES (regulated on T-cell activation, normal T-cell expressed and secreted), are known to inhibit human immunodeficiency virus (HIV) entry, and N-terminally modified RANTES analogues are more potent than native RANTES in blocking infection. However, potent CCR5 blocking agents may select for HIV-1 variants that use alternative coreceptors at less than fully inhibitory concentrations. In this study, two N-terminal chemical modifications of RANTES produced by total synthesis, aminooxypentane (AOP)-RANTES[2-68] and N-nonanoyl (NNY)-RANTES[2-68], were tested for their ability to prevent HIV-1 infection and to select for coreceptor switch variants in the human peripheral blood lymphocyte-SCID mouse model. Mice were infected with a CCR5-using HIV-1 isolate that requires only one or two amino acid substitutions to use CXCR4 as a coreceptor. Even though it achieved lower circulating concentrations than AOP-RANTES (75 to 96 pM as opposed to 460 pM under our experimental conditions), NNY-RANTES was more effective in preventing HIV-1 infection. However, in a subset of treated mice, these levels of NNY-RANTES rapidly selected viruses with mutations in the V3 loop of envelope that altered coreceptor usage. These results reinforce the case for using agents that block all significant HIV-1 coreceptors for effective therapy.
Mosier
D E
DE
Department of Immunology-IMM7, The Scripps Research Institute, La Jolla, California 92037, USA. dmosier@scripps.edu
Picchio
G R
GR
Gulizia
R J
RJ
Sabbe
R
R
Poignard
P
P
Picard
L
L
Offord
R E
RE
Thompson
D A
DA
Wilken
J
J
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004195:Disease Models, Animal; D014644:Genetic Variation; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D019380:Anti-HIV Agents; D018946:Chemokine CCL5; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C111989:aminooxypentane-RANTES