The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1

• Published in: PLoS pathogens 2013-12, Vol.9 (12), p.e1003852-e1003852
• Main Authors: Guzzo, Christina, Fox, Jamie, Lin, Yin, Miao, Huiyi, Cimbro, Raffaello, Volkman, Brian F, Fauci, Anthony S, Lusso, Paolo
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Blood banks; CD4 Antigens - metabolism; CD8-Positive T-Lymphocytes - immunology; Cell culture; Cells, Cultured; Chemokines; Chemokines, C - chemistry; Chemokines, C - immunology; Chemokines, C - pharmacology; Colleges & universities; Experiments; Health aspects; HIV; HIV (Viruses); HIV Envelope Protein gp120 - metabolism; HIV-1 - physiology; Host-parasite relationships; Human immunodeficiency virus; Humans; Infections; Lymphocytes; Medical research; Microbiological research; Physiological aspects; Protein Binding; Protein Conformation; Protein Folding; Proteins; Receptors, CCR5 - metabolism; Receptors, CXCR4 - metabolism; Structure-Activity Relationship; T cells; Virus Attachment - drug effects; Virus Internalization - drug effects
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003852

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.