HIV infection deregulates Tim-3 expression on innate cells: combination antiretroviral therapy results in partial restoration.

J Acquir Immune Defic Syndr. 2013 Jun 1;63(2):161-7.

Finney CA, Ayi K, Wasmuth JD, Sheth PM, Kaul R, Loutfy M, Kain KC, Serghides L.

SAR Laboratories, Sandra Rotman Centre for Global Health, UHN-Toronto General Hospital, Toronto, ON, Canada.

Abstract

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.

PMID: 23314411

 

Supplements:

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, including HIV.  Blocking Tim-3 has been proposed as a potential therapeutic intervention in HIV infection, with the objective of enhancing T-cell function.  However, Tim-3 expression and function in innate immunity have yet to be investigated in HIV infection, and this information would be of great importance before any therapeutic strategy targeting Tim-3 is to be considered.

Our study is the first to characterize Tim-3 expression in 4 different innate cell subsets in HIV-positive individuals prior to combination antiretroviral treatment initiation and 6 months following treatment initiation.  We characterized Tim-3 expression both in resting cells and also in response to malaria-infected erythrocytes as an inflammatory stimulus.  Our data show that Tim-3 levels and Tim-3 responses to stimuli are altered in innate immune cells in the presence of untreated HIV infection, and are only partially corrected by combination antiretroviral therapy. If Tim-3 is a marker of dysfunction on innate cells, as it has been demonstrated to be on CD4+ and CD8+ T cells, then our data may suggest that untreated HIV infection is associated with a more profound immune deficit that encompasses both adaptive and innate immune cells. Our data clearly indicate that further studies on Tim-3 expression and function in HIV-positive individuals will need to be carried out before stimulating or blocking Tim-3 can be considered a viable therapeutic strategy.

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