CCR8 on Human Thymocytes Functions as a Human Immunodeficiency Virus Type 1 Coreceptor

As a primary site for T-cell differentiation, maturation, and selection, the thymus plays a crucial role in early childhood. Infection with human immunodeficiency virus (HIV) induces severe thymic involution in pediatric patients and results in the depletion of mature and immature thymocytes (13, 24, 29). HIV type 1 (HIV-1)-induced thymic dysfunction is associated with a fast progression to AIDS in pediatric patients (22). CCR5-using (R5) viruses have been shown to infect mature thymocytes as well as thymic stromal cells, including macrophages, in vitro and in vivo in the SCID-hu mouse model (2, 14, 18, 35, 37). In contrast, in most cases CXCR4-using (X4) viruses have been shown to infect immature thymocytes and thymocyte precursors in vitro and to induce fast thymocyte depletion, with subsequent interruption of thymopoiesis, in vivo in SCID-hu mouse models (18, 31, 34, 35, 37, 38). Recent studies from our laboratory (42) and others (3, 17, 25, 44) have demonstrated that thymocytes express high levels of CXCR4 and low levels of CCR5 and that these receptors are involved in thymocyte infection with T-cell line-tropic and macrophage-tropic viruses, respectively (25, 42). Expression of chemokine receptor CCR8 and orphan receptors STRL33 and GPR15 has been detected in the thymus at the mRNA level (9, 20); however, whether these “minor” HIV-1 coreceptors are used in vivo for the infection of primary thymocytes or any other cell type is uncertain. CCR8 is a human receptor for the CC chemokine I-309 (28, 36). In addition to the thymus, CCR8 mRNA is expressed in human monocytes and Th2 lymphocytes (36, 47). CCR8 has been shown to support infection by diverse HIV-1 strains, including dualtropic viruses, in CCR8-transfected cell lines (15, 30, 45). Here, we address the role of CCR8 in primary human thymocytes.