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The pathways for differentiation of human CD[4.sup.+] T cells into functionally distinct subsets of memory cells in vivo are unknown. The identification of these subsets and pathways has clear implications for the design of vaccines and immune-targeted therapies. Here, we show that populations of apparently naive CD[4.sup.+] T cells express the chemokine receptors CXCR3 or CCR4 and demonstrate patterns of gene expression and functional responses characteristic of memory cells. The proliferation history and T cell receptor repertoire of these chemokine-[receptor.sup.+] cells suggest that they are very early memory CD[4.sup.+] T cells that have 'rested down' before acquiring the phenotypes described for 'central' or 'effector' memory T cells. In addition, the chemokine-[receptor.sup.+] 'naive' populations contain Th1 and Th2 cells, respectively, demonstrating that Th1/Th2 differentiation can occur very early in vivo in the absence of markers conventionally associated with memory cells. We localized ligands for CXCR3 and CCR4 to separate foci in T cell zones of tonsil, suggesting that the chemokine-[receptor.sup.+] subsets may be recruited and contribute to segregated, polarized micro-environments within lymphoid organs. Importantly, our data suggest that CD[4.sup.+] T cells do not differentiate according to a simple schema from nalve [right arrow] CD45R[O.sup.+] noneffector/central memory effector/effector memory cells. Rather, developmental pathways branch early on to yield effector/memory populations that are highly heterogeneous and multifunctional and have the potential to become stable resting cells. chemokines | immunologic memory | Th1/Th2 cells

The HIV-1 Tat protein is a potent chemoattractant for monocytes. We observed that Tat shows conserved amino acids corresponding to critical sequences of the chemokines, a family of molecules known for their potent ability to attract monocytes. Synthetic Tat and a peptide ([CysL.sub.24-51]) encompassing the 'chemokine-like' region of Tat induced a rapid and transient [Ca.sup.2+] influx in monocytes and macrophages, analogous to [Beta]-chemokines. Both monocyte migration and [Ca.sup.2+] mobilization were pertussis toxin sensitive and cholera toxin insensitive. Cross-desensitization studies indicated that Tat shares receptors with MCP-1, MCP-3, and eotaxin. Tat was able to displace binding of [Beta]-chemokines from the [Beta]-chemokine receptors CCR2 and CCR3, but not CCR1, CCR4, and CCR5. Direct receptor binding experiments with the [CysL.sub.24-51] peptide confirmed binding to cells transfected with CCR2 and CCR3. HIV-1 Tat appears to mimic [Beta]-chemokine features, which may serve to locally recruit chemokine receptor-expressing monocytes/macrophages toward HIV producing cells and facilitate activation and infection.

It is shown that recombinant envelope proteins from macrophage-tropic human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), trigger a signal through CCR5 on CD4+ T cells, and that signal transduction induces chemotaxis of T cells. The response could contribute to HIV pathogenesis, by attracting CD4+ cells to viral replication sites.