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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e318285cf13
Basic and Translational Science

HIV Infection Deregulates Tim-3 Expression on Innate Cells: Combination Antiretroviral Therapy Results in Partial Restoration

Finney, Constance A.M. PhD*,†,‡; Ayi, Kodjo PhD*,†; Wasmuth, James D. MSc, PhD§; Sheth, Prameet M. PhD*,†; Kaul, Rupert MD, FRCPC, PhD*,†,‖; Loutfy, Mona MD, FRCPC, MPH¶,#; Kain, Kevin C. MD, FRCPC*,†; Serghides, Lena PhD*,†

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Background: The Tim-3 receptor has been implicated as a negative regulator of adaptive immune responses and has been linked to T-cell dysfunction in chronic viral infections, such as HIV. Blocking Tim-3 has been proposed as a potential therapeutic intervention in HIV infection. However, a more detailed characterization of Tim-3 expression in the presence of HIV is required before such strategies can be considered.

Methods: In this study, we investigate Tim-3 expression on innate immune cell subsets in chronic HIV-infected individuals pretherapy and posttherapy.

Results: We report that, pretherapy, HIV infection is associated with elevated levels of Tim-3 on resting innate lymphocytes (NK, NKT, and γδ T cells), but not resting monocytes. In the absence of HIV infection, stimulation with an inflammatory stimulus resulted in decreased Tim-3 on monocytes and increased Tim-3 on NK, NKT, and γδ T cells. However, innate cells from HIV-infected donors were significantly less responsive to stimulation. Six months of combination antiretroviral therapy (cART) restored Tim-3 levels on resting NK cells but not NKT or γδ T cells. The responses of all subsets to inflammatory stimuli were restored to some extent with cART but only reached HIV-negative control levels in monocytes and NK cells.

Discussion: These results demonstrate that, during HIV infection, Tim-3 expression on innate cells is dysregulated and that this dysregulation is only partially restored after 6 months of cART. Our findings suggest that Tim-3 is differentially regulated on innate immune effector cells, and have direct implications for strategies designed to block Tim-3–ligand interactions.

© 2013 by Lippincott Williams & Wilkins


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