HIV-1 Nef-Src Family Kinase Interaction: A Novel Target for the Inhibition of HIV-1 Pathogenesis

摘要: Human immunodeficiency virus-1 (HIV-1) is a lentivirus responsible for development of AIDS. In addition to typical retroviral proteins (Gag, Pol and Env), primate lentiviruses like HIV-1 encode two regulatory (Tat Rev) four accessory (Vif, Vpu, Vpr Nef). The factor Nef essential high-titer viral replication AIDS progression. function requires interaction with many host cell proteins, including specific members the Src kinase family. this dissertation project, I explored whether Src-family (SFK) activation conserved property nef alleles from wide range primary isolates its sensitivity selective pharmacological inhibitors. Representative major subtypes A1, A2, B, C, F1, F2, G, H, J K strongly activated Hck Lyn as well c-Src lesser extent, demonstrating first time that SFK highly M-group isolates. Moreover, patient-derived also Hck. Recently, our group identified 4-amino diphenylfuranopyrimidines (DFPs) diphenylpyrazolyldiazene (PPD-B9) compounds selectively inhibit Nef-dependent HIV replication. To determine these novel exhibit broad-spectrum antiretroviral activity against HIV-1, constructed chimeric forms strain NL4-3 expressing same 10 alleles. infectivity chimeras was indistinguishable wild-type in three distinct lines (MT2, U87MG CEM-T4). Importantly, 4-aminopropanol 4-aminobutanol derivatives DFP PPD-B9 potently inhibited all both CEM-T4 cells manner. effects correlated inhibition endogenous SFKs. My results demonstrate Hck, by among clades targeting pathway uniformly inhibits have strong public health significance developing therapeutics current drug resistant variants HIV-1.