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Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary
M Zaitseva1, A Blauvelt, S Lee
1Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Abstract:
Transmission of HIV-1 is predominantly restricted to macrophage (Mphi)-tropic strains. Langerhans cells (LCs) in mucosal epithelium, as well as macrophages located in the submucosal tissues, may be initial targets for HIV-1. This study was designed to determine whether restricted transmission of HIV-1 correlates with expression and function of HIV-1 co-receptors on LCs and macrophages. Using polyclonal rabbit IgGs specific for the HIV co-receptors cytokines CXCR4 and CCR5, we found that freshly isolated epidermal LCs (resembling resident mucosal LCs) expressed CCR5, but not CXCR, on their surfaces. In concordance with surface expression, fresh LCs fused with Mphi-tropic but not with T-tropic HIV-1 envelopes. However, fresh LCs did contain intracellular CXCR4 protein that was transported to the surface during in vitro culture. Macrophages expressed high levels of both co-receptors on their surfaces, but only CCR5 was functional in a fusion assay. These data provide several possible explanations for the selective transmission of Mphi-tropic HIV variants and for the resistance to infection conferred by the CCR5 deletion.
Insights
Human immunodeficiency virus type 1 (HIV-1) primarily infects macrophages via M-tropic strains. This study reveals that Langerhans cells express CCR5, facilitating M-tropic HIV-1 fusion, while macrophages show functional CCR5, explaining selective HIV-1 transmission.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human immunodeficiency virus type 1 (HIV-1) transmission is often restricted to macrophage (Mphi)-tropic strains.
- Langerhans cells (LCs) in mucosal epithelium and submucosal macrophages are potential initial targets for HIV-1.
Purpose of the Study:
- To investigate the correlation between HIV-1 co-receptor expression and function on LCs and macrophages and the restricted transmission of HIV-1.
- To determine the role of CXCR4 and CCR5 in HIV-1 entry into these cells.
Main Methods:
- Freshly isolated epidermal LCs and macrophages were analyzed for surface and intracellular expression of HIV-1 co-receptors (CXCR4 and CCR5) using specific antibodies.
- Fusion assays were performed using HIV-1 envelopes (M-tropic and T-tropic) to assess co-receptor functionality.
Main Results:
- Epidermal LCs expressed CCR5 but not CXCR4 on their surface, fusing with M-tropic but not T-tropic HIV-1 envelopes.
- Intracellular CXCR4 was detected in fresh LCs and transported to the surface during in vitro culture.
- Macrophages expressed both CCR5 and CXCR4, but only CCR5 demonstrated functionality in fusion assays.
Conclusions:
- The expression profile of CCR5 on LCs and macrophages contributes to the selective transmission of M-tropic HIV-1 variants.
- Functional CCR5 on macrophages and its presence on LCs may explain the observed patterns of HIV-1 transmission and resistance associated with CCR5 deletion.