DIFFERENTIAL TROPISM AND REPLICATION KINETICS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ISOLATES IN THYMOCYTES - CORECEPTOR EXPRESSION ALLOWS VIRAL ENTRY, BUT PRODUCTIVE INFECTION OF DISTINCT SUBSETS IS DETERMINED AT THE POST-ENTRY LEVEL

Human thymocytes are readily infected with human immunodeficiency viru s type 1 (HIV-1) in vivo and in vitro. In this study, we found that th e kinetics of replication and cytopathic effects of two molecular isol ates, NL4-3 and JR-CSF, in postnatal thymocytes are best explained by the distribution of chemokine receptors used for viral entry. CXCR4 wa s expressed at high levels on most thymocytes, whereas CCR5 expression was restricted to only 0.1 to 2% of thymocytes. The difference in the amount of proviral DNA detected after infection of fresh thymocytes w ith NL4-3 or JR-CSF correlated with the levels of CXCR4 and CCR5 surfa ce expression. Anti-CCR5 blocking studies showed that low levels of CC R5 were necessary and sufficient for JR-CSF entry in thymocytes. Inter leukin-2 (IL-2), IL-4, and IL-7, cytokines normally present in the thy mus, influenced the expression of CXCR4 and CCR5 on thymocytes and thu s increased the infectivity and spread of bath NL4-3 and JR-CSF in cul ture. NL4-3 was produced by both immature and mature thymocytes, where as JR-CSF production was restricted to the mature CD1(-)/CD69(+) popul ation. Although CXCR4 and CCR5 distribution readily explained viral en try in mature CD69(+) and immature CD69(-) cells, and correlated with proviral DNA distribution, we found that viral production was favored in CD69(+) cells. Therefore, while expression of CD4 and appropriate c oreceptors are essential determinants of viral entry, factors related to activation and stage-specific maturation contribute to HIV-1 replic ation in thymocyte subsets. These results have direct implications for HIV-1 pathogenesis in pediatric patients.