Human immunodeficiency virus persistence and production in T-cell development

Human immunodeficiency virus type 1 (HIV-1) replication depends on CD4 and coreceptor expression as well as host factors associated with the activation state of the cell. To determine the impact of the activation stage of thymocytes on the HIV-1 life cycle, we investigated R5 and X4 HIV-1 entry, reverse transcription, and expression in discrete thymocyte subsets at different stages of T-cell development. Early after infection, preferential entry and replication of R5 HIV-1 were predominantly detected in mature CD3(+/hi)CD27(+) thymocytes. Thus, R5 HIV-1 targets the stage of development where thymocytes acquire functional responsiveness, which has important implications for HIV pathogenesis. In contrast, X4 HIV-1 expression and replication were primarily found in immature CD3(-/+/low) CD27(-) CD69(-) thymocytes. HIV-1 proviral burden and virus expression in thymocyte subsets correlated with the expression of the highest levels of the respective coreceptor. R5 and X4 HIV-1 entered and completed reverse transcription in all subsets tested, indicating that the activation state of thymocytes and coreceptor expression are sufficient to support full reverse transcription throughout development. Although R5 HIV-1 is expressed mainly in mature CD3(+/hi)CD27(+) thymocytes, 53% of HIV-1-infected immature thymocytes express R5 HIV-1, indicating that potentially latent viral DNA can be established early in T-cell development.