MULTIPLE EXTRACELLULAR DOMAINS OF CCR-5 CONTRIBUTE TO HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENTRY AND FUSION

Human immunodeficiency virus type 1 (HIV-1) entry is governed by the i nteraction of the viral envelope glycoprotein (Env) with its receptor, The HIV-1 receptor is composed of two molecules, the CD4 binding rece ptor and a coreceptor. The seven-membrane-spanning chemokine receptor CCR-5 is one of the coreceptors used by primary isolates of HIV-1, We demonstrate that the mouse homolog of CCR-5 (mCCR-5) does not function as an HIV-1 coreceptor, A set of chimeras of human CCR-5 and mCCR-5 w as studied for Env-induced cell fusion and HIV-1 infection. Using the HIV-1(ADA) envelope glycoprotein in a syncytium formation assay, we sh ow that replacement of any fragment containing extracellular domains o f mCCR-5 by its human counterparts is sufficient to allow Env-induced fusion, Conversely, replacement of any fragment containing human extra cellular domains by its murine counterpart did not lead to coreceptor function loss. These results show that several domains of CCR-5 partic ipate in coreceptor function, In addition, using a panel of primary no nsyncytium-inducing and syncytium-inducing isolates that use CCR-5 or both CXCR-4 and CCR-5 as coreceptors, we show that the latter dual-tro pic isolates are less tolerant to changes in CCR-5 than strains with a more restricted coreceptor use. Thus, different strains are likely to have different ways of interacting with the CCR-5 coreceptor.