Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remai...Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.展开更多
Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous p...Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.展开更多
基金supported by the DFG(CRC 1279)the NIH(AI164570,P30 AI045008)+2 种基金the Robert I.Jacobs Fund of the Philadelphia Foundation(LM),and a Herbert Kean,M.D.,Family Professorship(LM)Additionally,we thank the Human Immunology Core(HIC)at the Perelman School of Medicine at the University of Pennsylvania for their support with the Simoa assay,with partial funding from NIH P30 AI045008 and P30 CA016520The HIC is also supported by NIH grants and is identified by RRID:SCR_022380.G.M.L.was supported by NIH U24AI143502.
文摘Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.
基金supported by the German Research Foundation(DFG)through the CRC1279supported by the DFG under Germany’s Excellence Strategy-EXC 2033-390677874-RESOLVby the Boehringer Ingelheim Foundation(Plus-3 Program)
文摘Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.
