Chimpanzee CXCR4 and CCR5 act as coreceptors for HIV type 1.

Chemokine receptors are molecules involved in the fusion of immunodeficiency viruses after their attachment. As chimpanzees are the animal model for infection by HIV-1, we cloned and sequenced chimpanzee CXCR4 and CCR5 from PBMCs. Chimpanzee CXCR4 was found to be identical to human CXCR4, which provides an explanation for the sensitivity of chimpanzees to lymphotropic isolates of HIV-1. Chimpanzee CCR5 showed two substitutions with respect to human CCR5. However, we show that the macrophage-tropic isolate HIV-1-Ba-L can use chimpanzee CCR5 as a fusion receptor. Therefore, the resistance of chimpanzee PBMCs to infection by macrophage-tropic isolates of HIV-1 is unlikely to be due to substitutions in CCR5.

CD4-mediated enhancement or inhibition of T cell activation does not require the CD4:p56lck association.

CD4 is the coreceptor molecule expressed on the surface of T cells specific for or restricted by class II molecules of the major histocompatibility complex (MHC). Its expression on T cells is required for an optimal response to antigen (Ag). Three mechanisms have been invoked for the involvement of CD4 in T cell activation. First, it was shown that CD4 binds to MHC class II molecules on antigen presenting cells (APCs) thereby favoring an adhesion between effector cells and APCs. Association of CD4 to the T cell receptor and to the tyrosine kinase p56lck have also been shown to be critically involved in the positive function of CD4. Here, we demonstrate that the interaction of CD4 with p56lck is not required to enhance the response of two CD4-dependent, Ag-specific T cell hybridomas. Mutant forms of CD4 (TCD4), which lose association to p56lck, were expressed in these T cells and were shown to enhance the Ag-specific response as efficiently as the wild-type CD4. Moreover both CD4-dependent and independent T cell responses were inhibited by CD4-specific mAbs even when CD4 was not associated with p56lck. These results indicate that mechanisms distinct from sequestration of p56lck and/or negative signaling operate in these inhibitions. Results demonstrating enhancement of TCR-mediated signaling by the coaggregation of TCD4 mutant to the TCR further confirm that the association of p56lck to CD4 is not absolutely required for the regulatory functions of CD4. Our results suggest that the mechanisms implicated in the enhancement of T cell stimulation via CD4 depend solely on the extracellular and transmembrane domains of CD4.