title: The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.
abstract: CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES) are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative). We found that XCL1 inhibits a broad spectrum of HIV-1 isolates, irrespective of their coreceptor-usage phenotype. Experiments with stabilized variants of XCL1 demonstrated that HIV-1 inhibition requires access to the alternative, all-β conformation, which interacts with proteoglycans but does not bind/activate the specific XCR1 receptor, while the classic XCL1 conformation is inactive. HIV-1 inhibition by XCL1 was shown to occur at an early stage of infection, via blockade of viral attachment and entry into host cells. Analogous to the recently described anti-HIV effect of the CXC chemokine CXCL4/PF4, XCL1-mediated inhibition is associated with direct interaction of the chemokine with the HIV-1 envelope. These results may open new perspectives for understanding the mechanisms of HIV-1 control and reveal new molecular targets for the design of effective therapeutic and preventive strategies against HIV-1.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Guzzo
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Jamie
authors.initials: J
authors.lastname: Fox
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Huiyi
authors.initials: H
authors.lastname: Miao
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Raffaello
authors.initials: R
authors.lastname: Cimbro
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lusso
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D019744:Chemokines, C / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013329:Structure-Activity Relationship; D053585:Virus Attachment / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects
chemical_list: C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D019744:Chemokines, C; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C092390:XCL1 protein, human; C514793:gp120 protein, Human immunodeficiency virus 1