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 inflammator y protein 1 alpha (MIP-1 alpha), MIP-1 beta, and RANTES (regulated on T-cel l activation, normal T-cell expressed and secreted), are known to inhibit h uman immunodeficiency virus (HM entry, and N-terminally modified RANTES ana logues are more potent than native RANTES in blocking infection. However, p otent CCR5 blocking agents may select for HIV-1 variants that use alternati ve coreceptors at less than fully inhibitory concentrations. In this study, two N-terminal chemical modifications of RANTES produced by total synthesi s, aminooxypentane (AOP)-RANTES[2-68] and N-nonanoyl (NNY)-RANTES[2-68], we re tested for their ability to prevent HIV-1 infection and to select for co receptor switch variants in the human peripheral blood lymphocyte-SCID mous e model. Mice were infected with a CCR5-using HIV-1 isolate that requires o nly one or two amino acid substitutions to use CXCR4 as a coreceptor, Even though it achieved lon er 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 t reated mice, these levels of NNY-RANTES rapidly selected viruses with mutat ions in the V3 loop of envelope that altered coreceptor usage. These result s reinforce the case for using agents that block all significant HIV-1 core ceptors for effective therapy.