HIV-1 Infection Results in Sphingosine-1-Phosphate Receptor 1 Dysregulation in the Human Thymus

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Regeneration of functional T lymphocytes is critical for people living with HIV (PLWH), even on antiretroviral therapy (ART).
• Limited data exists on HIV-1's impact on thymic precursor entry and T lymphocyte egress from the thymus.
• Sphingosine-1-phosphate (S1P) signaling regulates the egress of naïve thymocytes.

Purpose of the Study:

• To investigate the impact of HIV-1 on S1P signaling and T cell egress from the thymus.
• To determine if HIV-1 infection affects S1P receptor 1 (S1PR1) expression in the human thymus.

Main Methods:

• In vitro studies using primary human thymocytes.
• In vivo and ex vivo studies with humanized mice models.
• Analysis of S1PR1 expression and cytokine profiles in infected thymic tissues.

Main Results:

• HIV-1 infection upregulates S1PR1 expression in the human thymus, both in intrathymic and systemic infections.
• Cytokine dysregulation, specifically Interferon-Beta (IFN-β) and Tumor Necrosis Factor-Alpha (TNF-α), correlates with increased S1PR1 expression.
• Increased presence of mature and less mature T cells in the spleen of infected humanized mice suggests accelerated thymocyte egress.

Conclusions:

• HIV-1 infection dysregulates S1P signaling by upregulating S1PR1 in the thymus.
• This upregulation may lead to accelerated or increased egress of thymocytes, including immature T cells.
• Premature egress of functionally immature T cells could compromise immune function in PLWH.