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
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.
