CXCR4 AND CCR5 ON HUMAN THYMOCYTES - BIOLOGICAL FUNCTION AND ROLE IN HIV-1 INFECTION

Thymocyte infection with HIV-1 is associated with thymic involution an d impaired thymopoiesis, particularly in pediatric patients. To define mechanisms of thymocyte infection,,ve examined human thymocytes for e xpression and function of CXCR4 and CCR5, the major cell entry corecep tors for T cell line-tropic (T-tropic) and macrophage-tropic (M-tropic ) strains of HIV-1, respectively, CXCR4 was detected on the surface of all thymocytes, CXCR4 expression on mature, high level TCR thymocytes was similar to that on peripheral blood T cells, but,vas much lower t han that on immature thymocytes, including CD34(+) thymic progenitors. Consistent with this, stroma-derived factor-1 (SDF-1) induced calcium flux primarily in immature thymocytes, with CD34(+) progenitors givin g the strongest response, In addition, SDF-1 mRNA was detected in thym ic-derived stromal cells, and SDF-1 induced chemotaxis of thymocytes, suggesting that CXCR4; may play a role in thymocyte migration. Infecti on of immature thymocytes by the T-tropic HIV-1 strain LAI was 10-fold more efficient than that in mature thymocytes, consistent with their relative CXCR4 surface expression. Anti-CXCR4 antiserum or SDF-1 block ed fusion of thymocytes with cells expressing the LAI envelope. In con trast to CXCR4, CCR5 was detected at low levels on thymocytes, and CCR 5 agonists did not induce calcium flux of chemotaxis in thymocytes, Ho wever, CD4(+) mature thymocytes;were productively infected with the CC R5-tropic strain Ba-L, and this infection was specifically inhibited w ith the CCR5 agonist, macrophage inflammatory protein-1 beta. Our data provide strong evidence that CXCR4 and CCR5 function as coreceptors f or HIV-1. infection of human thymocytes.