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Chemokines, lymphocytes, and HIV
1Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-1888, USA. joshua_farber@nih.gov
Insights
Chemokines and their receptors are crucial for lymphocyte function and HIV-1 entry. This study characterizes Mig, Crg-2/IP-10, CCR6, and STRL33, revealing their roles in immune responses and potential therapeutic targets.
Area of Science:
- Immunology and Virology
- Cytokine and Chemokine Research
Background:
- Chemokines are cytokines involved in leukocyte recruitment, with poorly understood roles in lymphocyte biology.
- Recent discoveries link chemokines and their receptors to HIV-1 suppression and entry, highlighting their importance.
Purpose of the Study:
- To investigate the roles of chemokines and their receptors in lymphocyte biology.
- To characterize specific chemokines (Mig, Crg-2/IP-10) and receptors (STRL22/CCR6, STRL33) involved in immune responses.
Main Methods:
- Characterization of Mig and Crg-2/IP-10 chemokines induced by IFN-gamma.
- Gene expression analysis during experimental infections in mice.
- Cloning and functional analysis of lymphocyte-expressed chemokine receptors STRL22 and STRL33.
Main Results:
- Mig and Crg-2/IP-10 are induced by IFN-gamma and target activated T cells, with distinct in vivo expression patterns suggesting non-redundant roles.
- STRL22 was identified as CCR6, a receptor for MIP-3 alpha.
- STRL33 functions as an HIV-1 co-receptor, active with a broad range of viral envelope glycoproteins.
Conclusions:
- Chemokines and their receptors play significant roles in lymphocyte biology and immune responses.
- STRL33's broad co-receptor activity offers potential for novel anti-HIV-1 therapies.
- Further research into chemokines and lymphocyte interactions is vital for understanding AIDS pathogenesis and manipulating immune responses.
Abstract:
Chemokines are members of a family of more than 30 human cytokines whose best-described activities are as chemotactic factors for leukocytes and that are presumed to be important in leukocyte recruitment and trafficking. While many chemokines can act on lymphocytes, the roles of chemokines and their receptors in lymphocyte biology are poorly understood. The recent discoveries that chemokines can suppress infection by HIV-1 and that chemokine receptors serve, along with CD4, as obligate co-receptors for HIV-1 entry have lent urgency to studies on the relationships between chemokines and lymphocytes. My laboratory has characterized Mig and Crg-2/IP-10, chemokines that are induced by IFN-gamma and that specifically target lymphocytes, particularly activated T cells. We have demonstrated that the genes for these chemokines are widely expressed during experimental infections in mice with protozoan and viral pathogens, but that the patterns of mig and crg-2 expression differed, suggesting non-redundant roles in vivo. Our related studies to identify new chemokine receptors from activated lymphocytes resulted in the cloning of STRL22 and STRL33. We and others have shown that STRL22 is a receptor for the CC chemokine MIP-3 alpha, and STRL22 has been renamed CCR6. Although STRL33 remains an orphan receptor, we have shown that it can function as a co-receptor for HIV-1 envelope glycoproteins, and that it is active with a broader range of HIV-1 envelope glycoproteins than the major co-receptors described to date. The ability of STRL33 to function with a wide variety of envelope glycoproteins may become particularly important if therapies are instituted to block other specific co-receptors. We presume that investigations into the roles of chemokines and their receptors in lymphocyte biology will provide information important for understanding the pathogenesis of AIDS and for manipulating immune and inflammatory responses for clinical benefit.