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 Postentry Level

Abstract

Human thymocytes are readily infected with human immunodeficiency virus type 1 (HIV-1) in vivo and in vitro. In this study, we found that the kinetics of replication and cytopathic effects of two molecular isolates, NL4-3 and JR-CSF, in postnatal thymocytes are best explained by the distribution of chemokine receptors used for viral entry. CXCR4 was 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 with NL4-3 or JR-CSF correlated with the levels of CXCR4 and CCR5 surface expression. Anti-CCR5 blocking studies showed that low levels of CCR5 were necessary and sufficient for JR-CSF entry in thymocytes. Interleukin-2 (IL-2), IL-4, and IL-7, cytokines normally present in the thymus, influenced the expression of CXCR4 and CCR5 on thymocytes and thus increased the infectivity and spread of both NL4-3 and JR-CSF in culture. NL4-3 was produced by both immature and mature thymocytes, whereas JR-CSF production was restricted to the mature CD1−/CD69+ population. Although CXCR4 and CCR5 distribution readily explained viral entry 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 coreceptors are essential determinants of viral entry, factors related to activation and stage-specific maturation contribute to HIV-1 replication in thymocyte subsets. These results have direct implications for HIV-1 pathogenesis in pediatric patients.

Coreceptor Competition for Association with CD4 May Change the Susceptibility of Human Cells to Infection with T-Tropic and Macrophagetropic Isolates of Human Immunodeficiency Virus Type 1

“…Coreceptor competition may also explain earlier studies with human thymocytes in which preferential infection of doublepositive thymocytes with T-tropic viruses was observed (3,21,28,33), despite expression of low-level CCR5 in both doublepositive and single-positive thymocyte subpopulations as recently demonstrated (39). Significantly higher expression of CXCR4 compared with CCR5 was found on immature doublepositive thymocytes (but not on the mature single-positive thymocytes) (21,39).…”

“…Together, these data contribute to understanding the possible effects of in vivo alterations in CD4 and coreceptor densities (or coreceptor availability) on HIV-1 cell entry and disease progression. Furthermore, the development of ␤-chemokine analogs as antiviral agents (28,32,35) should take into account their potential to alter coreceptor-CD4 interactions and to alter the susceptibility of target cells to infection with viruses of different coreceptor usage (2,27,31).…”

Developmental regulation of P-glycoprotein activity within thymocytes results in increased anti-HIV protease inhibitor activity

“…HIV-1 variants replicating in the thymus predominantly use CXCR4 as their coreceptor [3,4,50]. We have shown recently that the thymus plays a key role in the evolution of CXCR4 variants found in the thymus, blood, and tissues [5].…”

“…The thymus, the primary lymphoid organ involved in T cell maturation and differentiation, is an important tissue target for HIV-1 infection [1,2]. Thymocytes are susceptible to infection in vivo and ex vivo, predominantly by viruses that use the CXCR4 coreceptor, providing a milieu for emergence of these viruses in vivo [3][4][5][6]. As a result, HIV-1 infection leads to decreased thymic output and aberrant T cell maturation [7,8].…”

Thymocyte-Thymic Epithelial Cell Interaction Leads to High-Level Replication of Human Immunodeficiency Virus Exclusively in Mature CD4+CD8−CD3+Thymocytes: a Critical Role for Tumor Necrosis Factor and Interleukin-7

“…In the SCID-hu mouse model, viral DNA sequences were detected by PCR analysis in all the thymocytes expressing the CD4 receptor (30,49). However, the kinetics of replication in the different subpopulations was shown to vary according to the viral isolates (10,49), and this is very probably related to the distribution of the chemokine receptors on the human thymocyte subsets and to their usage by the viral isolates (9,31,42,64). However, an efficient entry of the virus does not necessarily lead to a productive infection.…”