CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as defined by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp120 results in modulation of both CCR5 and CXCR4 responsiveness, which is dependent upon p56lck enzymatic activity. The recent findings that pretreatment of T cells with a natural CD4 ligand, IL-16, could alter cellular responsiveness to macrophage-inflammatory protein-1β (MIP-1β) stimulation, prompted us to investigate whether IL-16 could also alter CXCR4 signaling. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1α (SDF-1α)/CXCR4-induced chemotaxis; however, unlike MIP-1β/CCR5, the effects were not reciprocal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitization of CXCR4 by IL-16 required at least 10–15 min pretreatment; no modulation of CXCR4 expression was observed, nor was SDF-1α binding altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56lck-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1β/CCR5 responses requires p56lck enzymatic activity. IL-16/CD4 inhibition of SDF-1α/CXCR4 signals requires the presence of the Src homology 3 domain of p56lck and most likely involves activation of phosphatidylinositol-3 kinase. These studies indicate the mechanism of CXCR4 receptor desensitization induced by a natural ligand for CD4, IL-16, is distinct from the inhibitory effects induced by either gp120 or IL-16 on CCR5.

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The ability of HIV-1 gp120 to inhibit chemokine signaling prompted us to determine whether signaling through CD4 by a natural ligand, IL-16, could alter cellular responsiveness to chemokine stimulation. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes results in a selective loss of macrophage-inflammatory protein (MIP)-1β/CCR5-induced chemotaxis. There was no effect on monocyte chemoattractant protein-2/CCR1, -2, or -3-induced chemotaxis. Desensitization of CCR5 by IL-16 required at least 10 min of pretreatment; no modulation of CCR5 expression was observed, nor was MIP-1β binding to CCR5 altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56lck-dependent signal that results in desensitization of CCR5. The desensitization process is reciprocal and again selective, as prior CCR5 stimulation, but not CCR1, -2, or -3 stimulation, completely inhibits IL-16/CD4-induced T cell migration. Of interest, while p56lck enzymatic activity is not required for IL-16-induced migration, it was required for desensitization of CCR5. These studies indicate the existence of reciprocal receptor cross-desensitization between CD4 and CCR5 induced by two proinflammatory cytokines and suggest a selective relationship between the two receptors.

A case of viral transmission to the father of a newly vaccinated infant shows how the virtual disappearance of a once terrifying illness can obscure its recognition and how perplexing public health issues may arise when an invaluable vaccine is anything less than perfect.