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CCR8 on human thymocytes functions as a human immunodeficiency virus type 1 coreceptor
1Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Bethesda, Maryland 20892, USA.
Insights
The chemokine receptor CCR8 acts as a coreceptor for human immunodeficiency virus type 1 (HIV-1) infection in the thymus. This finding suggests CCR8 may play a role in HIV-1-related thymic pathogenesis.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human immunodeficiency virus type 1 (HIV-1) infects immune cells, including those in the thymus.
- CXCR4 and CCR5 are known HIV-1 coreceptors, but others may be involved in thymic infection.
Purpose of the Study:
- To investigate the role of CCR8, a thymus-expressed chemokine receptor, as an HIV-1 coreceptor.
- To determine if CCR8 contributes to HIV-1 pathogenesis in the thymus.
Main Methods:
- Quantification of CCR8 mRNA in immature and mature human thymocytes.
- Binding assays using radiolabeled I-309 (CCR8 ligand) on thymocytes.
- Fusion inhibition assays with HIV-1 envelope glycoproteins (X4, R5, X4R5).
- Productive HIV-1 infection assays in human thymocytes.
Main Results:
- CCR8 mRNA was detected at similar levels in immature and mature thymocytes.
- I-309 bound specifically to both immature and mature human thymocytes.
- I-309 inhibited thymocyte fusion with cells expressing X4 or X4R5 HIV-1 envelope glycoproteins.
- I-309 partially inhibited productive infection by X4, R5, and X4R5 HIV-1 strains.
Conclusions:
- CCR8 functions as an HIV-1 coreceptor on primary human thymocytes.
- CCR8 may contribute to HIV-1-induced pathogenesis within the thymus.
Abstract:
To determine whether human immunodeficiency virus type 1 (HIV-1) coreceptors besides CXCR4 and CCR5 are involved in HIV-1 infection of the thymus, we focused on CCR8, a receptor for the chemokine I-309, because of its high expression in the thymus. Similar levels of CCR8 mRNA were detected in immature and mature primary human thymocytes. Consistent with this, [(125)I]I-309 was shown to bind specifically and with similar affinity to the surface of immature and mature human thymocytes. Fusion of human thymocytes with cells expressing HIV-1 X4 or X4R5 envelope glycoprotein was inhibited by I-309 in a dose-dependent manner. In addition, I-309 partially inhibited productive infection of human thymocytes by X4, R5, and X4R5 HIV-1 strains. Our data provide the first evidence that CCR8 functions as an HIV-1 coreceptor on primary human cells and suggest that CCR8 may contribute to HIV-1-induced thymic pathogenesis.