HIV-1 infection results in upregulation of Sphingosine-1-phosphate receptor 1 in the human thymus

Abstract Regeneration of functional naïve T lymphocytes following the onset of infection remains a crucial issue for HIV + individuals, even while adhering to Antiretroviral Therapy (ART). Thus far, reports on the impact of HIV-1 infection on the entry of thymic precursors and the egress of functional naïve T lymphocytes are limited. Therefore, we examined the impact of HIV-1 on Sphingosine-1-phosphate (S1P) signaling, which governs the egress of functional naïve thymocytes from the thymus to the periphery. Using in vitro experiments with primary human thymocytes and in vivo and ex vivo studies with humanized mice, we demonstrate that HIV-1 infection upregulates the expression of S1P receptor 1 (S1PR1) in the human thymus. Intriguingly, this upregulation occurs both during intrathymic infection (direct infection of the human thymic implant) as well as systemic infection in humanized mice. Moreover, the increase in pro-inflammatory cytokines in infected thymi and the upregulation of S1PR1 in response to in vitro exposure to Interferon-Beta (IFN-β) and Tumor Necrosis Factor-Alpha (TNF-α) indicate that the cytokine dysregulation following HIV infection may contribute to upregulation of S1PR1. Finally, an increased presence of CD3hiCD69- (fully mature) as well as CD3hiCD69+ (less mature) T cells in the spleen during HIV infection in humanized mice, as well as an earlier expression during thymocyte development, indicate that the upregulation of this receptor translates to increased and accelerated egress from the thymus. The egress of thymocytes that are not functionally mature from the thymus to peripheral blood and lymphoid organs may have implications for the immune function of people living with HIV (PLWH).