SPONTANEOUS MUTATIONS IN THE ENV GENE OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 NDK ISOLATE ARE ASSOCIATED WITH A CD4-INDEPENDENT ENTRY PHENOTYPE

Human immunodeficiency virus type 1 (HIV-1) entry into target cells is a multistep process initiated by envelope protein gp120 binding to ce ll surface CD4. The conformational changes induced by this interaction likely favor a second-step interaction between gp120 and a coreceptor such as CXCR4 or CCR5. Here, we report a spontaneous and stable CD4-i ndependent entry phenotype for the HIV-1 NDK isolate. This mutant stra in, which emerged from a population of chronically infected CD4-positi ve CEM cells, can replicate in CD4-negative human cell lines. The pres ence of CXCR4 alone renders cells susceptible to infection by the muta nt NDK, and infection can be blocked by the CXCR4 natural ligand SDF-1 . Furthermore, we have correlated the CD4-independent phenotype with s even mutations in the C2 and C3 regions and the V3 loop. We propose th at the mutant gp120 spontaneously acquires a conformation allowing it to interact directly with CXCR4. This virus provides us with a powerfu l tool to study directly gp120-CXCR4 interactions.