Highly Potent RANTES Analogues either Prevent CCR5-Using Human Immunodeficiency Virus Type 1 Infection In Vivo or Rapidly Select for CXCR4-Using Variants

• DOI: 10.1128/jvi.73.5.3544-3550.1999
• Publication Date: 2019-12-31T18:26:57Z
• Authors: Donald E. Mosier; Gastón R. Picchio; Richard J. Gulizia; Rebecca Sabbe; Pascal Poignard; Laurent Picard; Robin E. Offord; Darren A. Thompson; Jill Wilken
• Keywords: Receptors, CXCR4; 0303 health sciences; Receptors, CCR5; Sequence Homology, Amino Acid; Anti-HIV Agents; Molecular Sequence Data; Genetic Variation; HIV Infections; Mice, SCID; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; HIV-1; Animals; Humans; Amino Acid Sequence; Chemokine CCL5

ABSTRACT

The natural ligands for the CCR5 chemokine receptor, macrophage inflammatory protein 1α (MIP-1α), MIP-1β, 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.