Abstract: Methods are provided for treating a patient with viral-based gene therapy that promote persistent transgene expression. The methods include administering to the patient an inhibitor of the interleukin-6 (IL6) signaling pathway or the NCOR2/SMRT histone deacetylation pathway, and a viral-based gene therapy vector. Methods are also provided for assigning viral-based gene therapy to a patient that include determining whether the patient has a genotype sensitizing the patient to persistent infection by a viral-based gene therapy vector by evaluating whether the patient has a mutation in the SMRT/NCOR2 gene associated with reduced SMRT/NCOR2 protein function or in the interleukin-6 receptor (IL-6R) gene associated with reduced IL-6R function. If the patient has either a mutation in the SMRT/NCOR2 gene associated with reduced SMRT/NCOR2 protein function or a mutation in the IL-6R gene associated with reduced IL-6R function, a viral-based gene therapy vector is assigned to the patient.