Dataset Information

A new obligate CXCL4-CXCL12 heterodimer for studying chemokine heterodimer activities and mechanisms.

ABSTRACT: Chemokines form a family of proteins with critical roles in many biological processes in health and disease conditions, including cardiovascular, autoimmune diseases, infections, and cancer. Many chemokines engage in heterophilic interactions to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer-forming chemokines. In mixtures, different chemokine species with diverse activities coexist in dynamic equilibrium, leading to the observation of their combined response in biological assays. To overcome this problem, we produced a non-dissociating CXCL4-CXCL12 chemokine heterodimer OHD_4-12 as a new tool for studying the biological activities and mechanisms of chemokine heterodimers in biological environments. Using the OHD_4-12, we show that the CXCL4-CXCL12 chemokine heterodimer inhibits the CXCL12-driven migration of triple-negative MDA-MB-231 breast cancer cells. We also show that the CXCL4-CXCL12 chemokine heterodimer binds and activates the CXCR4 receptor.

SUBMITTER: Nguyen KTP

PROVIDER: S-EPMC9561612 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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A new obligate CXCL4-CXCL12 heterodimer for studying chemokine heterodimer activities and mechanisms.

Nguyen Khanh T P KTP Volkman Brian B Dréau Didier D Nesmelova Irina V IV

Scientific reports 20221013 1

Chemokines form a family of proteins with critical roles in many biological processes in health and disease conditions, including cardiovascular, autoimmune diseases, infections, and cancer. Many chemokines engage in heterophilic interactions to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer-forming chemokines. In mixtures, different chemokine species with diverse activities coexist in dynamic equilibrium, leading to the observa ...[more]

PMID: 36229490

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Project description:HIV-1 infects CD4 T lymphocytes (CD4TL) through binding the chemokine receptors CCR5 or CXCR4. CXCR4-using viruses are considered more pathogenic, linked to accelerated depletion of CD4TL and progression to AIDS. However, counterexamples to this paradigm are common, suggesting heterogeneity in the virulence of CXCR4-using viruses. Here, we investigated the role of the CXCR4 chemokine CXCL12 as a driving force behind virus virulence. In vitro, CXCL12 prevents HIV-1 from binding CXCR4 and entering CD4TL, but its role in HIV-1 transmission and propagation remains speculative. Through analysis of thirty envelope glycoproteins (Envs) from patients at different stages of infection, mostly treatment-naïve, we first interrogated whether sensitivity of viruses to inhibition by CXCL12 varies over time in infection. Results show that Envs resistant (RES) to CXCL12 are frequent in patients experiencing low CD4TL levels, most often late in infection, only rarely at the time of primary infection. Sensitivity assays to soluble CD4 or broadly neutralizing antibodies further showed that RES Envs adopt a more closed conformation with distinct antigenicity, compared to CXCL12-sensitive (SENS) Envs. At the level of the host cell, our results suggest that resistance is not due to improved fusion or binding to CD4, but owes to viruses using particular CXCR4 molecules weakly accessible to CXCL12. We finally asked whether the low CD4TL levels in patients are related to increased pathogenicity of RES viruses. Resistance actually provides viruses with an enhanced capacity to enter naive CD4TL when surrounded by CXCL12, which mirrors their situation in lymphoid organs, and to deplete bystander activated effector memory cells. Therefore, RES viruses seem more likely to deregulate CD4TL homeostasis. This work improves our understanding of the pathophysiology and the transmission of HIV-1 and suggests that RES viruses' receptors could represent new therapeutic targets to help prevent CD4TL depletion in HIV+ patients on cART.

Dataset Information

A new obligate CXCL4-CXCL12 heterodimer for studying chemokine heterodimer activities and mechanisms.

Publications

A new obligate CXCL4-CXCL12 heterodimer for studying chemokine heterodimer activities and mechanisms.

Similar Datasets

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