HIV Infection and Persistence in Pulmonary Mucosal Double Negative T Cells In Vivo

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• The lungs are largely unexplored HIV reservoirs during antiretroviral therapy (ART).
• Double-negative (DN) T cells (CD4- CD8-) are implicated as cellular HIV reservoirs.
• Pulmonary HIV burden and impaired lung immunity in people living with HIV (PLWH) are significant concerns.

Purpose of the Study:

• To comprehensively analyze pulmonary versus blood DN T cells in PLWH on ART.
• To investigate the role of lung DN T cells as anatomical and cellular HIV reservoirs.
• To characterize HIV persistence in pulmonary DN T cells during long-term ART.

Main Methods:

• Analysis of bronchoalveolar lavage (BAL) fluid and peripheral blood from PLWH on ART and HIV-negative controls.
• Flow cytometry to characterize DN T cell phenotype, senescence, and activation markers.
• HIV DNA detection in sorted DN T cells.
• Studies in humanized bone marrow-liver-thymus (hu-BLT) mouse models.

Main Results:

• DN T cells were more frequent in the lungs than blood in both PLWH and HIV-negative individuals, with an effector memory phenotype.
• Pulmonary DN T cells in PLWH expressed higher levels of HLA-DR, CCR6, CXCR3, and PD-1 compared to blood.
• Pulmonary DN T cells harbored HIV DNA, and lung DN T cells showed higher infection frequencies in hu-BLT mice.

Conclusions:

• HIV infects and persists in pulmonary mucosal DN T cells early in infection.
• Lung DN T cells serve as a persistent cellular reservoir for HIV, even under suppressive ART.
• These findings highlight the lungs as a critical anatomical reservoir and DN T cells as key cellular reservoirs for HIV eradication strategies.