Impaired T-cell differentiation in the thymus at the early stages of acute pathogenic chimeric simian–human immunodeficiency virus (SHIV) infection in contrast to less pathogenic SHIV infection

Abstract One of the mechanisms by which HIV infection induces the depletion of CD4 + T cells has been suggested to be impairment of T-cell development in the thymus, although there is no direct evidence that this occurs. To examine this possibility, we compared T-cell maturation in the intrathymic progenitors between macaques infected with an acute pathogenic chimeric simian–human immunodeficiency virus (SHIV), which causes profound and irreversible CD4 + T-cell depletion, and macaques infected with a less pathogenic SHIV, which causes only a transient CD4 + T-cell decline. Within 27 days post-inoculation (dpi), the two virus infections caused similar increases in plasma viral loads and similar decreases in CD4 + T-cell counts. However, in the thymus, the acute pathogenic SHIV resulted in increased thymic involution, atrophy and the depletion of immature T cells including CD4 + CD8 + double-positive (DP) cells, whereas the less pathogenic SHIV did not have these effects. Ex vivo differentiation of CD3 − CD4 − CD8 − triple-negative (TN) intrathymic progenitors to DP cells was assessed by a monkey–mouse xenogenic fetal thymus organ culture system. Differentiation was impaired in the TN intrathymic progenitors of the acute pathogenic SHIV-infected monkeys, while differentiation was not impaired in the TN intrathymic progenitors of the less pathogenic SHIV-infected monkeys. These differences suggest that dysfunction of thymic maturation makes an important contribution to the irreversible depletion of circulating CD4 + T cells in vivo.