The disclosure provides methods of reprogramming polyclonal T cells to maintain long-term persistence. The disclosure further provides methods of treatment, such as adoptive T cell transfer therapies, that harness Tscms for development of tumor-reactive T cells. In some embodiments, the disclosure provides methods and compositions for positive modulation of the Tscm-producing phenotype, e.g., positive modulation of TCF7 expression. Positive modulation of TCF7 expression allows for maintenance of an increased T number of stem-like T cells capable of both self-renewal and generation of differentiated, cytolytic progeny.

A synthetic lentiviral vector construct comprises a genomic RNA packaging enhancer (GRPE) element and lentiviral nucleic acid sequences sufficient for reverse transcription and packaging in a host cell.

Novel lentivirus packaging systems engineered with a synthetic gene network having a positive feedback loop to amplify the expression of virus genes are provided. When co-transfected into a host cell with a transfer plasmid and envelope vector, extremely high viral titers are achieved when compared to transfection of a host cell with conventional third generation packaging systems. Methods for enhancing production of lentivirus, compositions comprising high titer lentivirus, and therapeutic methods based on delivery of lentiviral nucleic acid to target cells are also provided.

The present invention relates to methods for preparing virus-like particles comprising immunogenic cyclic dinucleotides and its use for treating cancer.

A synthetic lentiviral vector construct comprises a genomic RNA packaging enhancer (GRPE) element and lentiviral nucleic acid sequences sufficient for reverse transcription and packaging in a host cell.

The invention features pseudotyped viral particles (e.g., lentiviral or gammaretroviral particles) and compositions and methods of use thereof, where the viral particles comprise a VHH domain.

Methods of preventing or treating rheumatoid arthritis (RA) in a subject by introducing the DRB1*04:01.sup.K71E mutation that is resistant to RA. The resistant allele is introduced into the subject having or at risk of developing RA, using a HLA CRISPR/Cas9 vector that targets codon 71 in the HLA allele DRB1*04:01, introducing a single A to G point mutation in codon 71 by homology directed repair to alter the lysine at position 71 of the expressed protein to glutamic acid. This modified allele is affected in the subject's hematopoietic stem cells, which are then expanded and transplanted back into the patient. This microgene therapy confers RA-resistance via an autologous transplant. The invention includes isolated nucleic acids, vectors, recombinant viruses, cells, and pharmaceutical compositions to modify the HLA DRB1*04:01 allele.

The invention features pseudotyped viral particles (e.g., lentiviral or gammaretroviral particles) and compositions and methods of use thereof, where the viral particles comprise a VHH domain.

The present invention relates to a nucleic acid molecule comprising or consisting of a nucleic acid sequence encoding the vesicular stomatitis virus envelope glycoprotein (VSV-G) linked to a (poly)peptide comprising or consisting of a cell membrane-binding domain, said nucleic acid sequence comprising in 5 to 3 direction (a) a first sequence segment encoding an endoplasmic reticulum (ER) signal sequence; (b) a second sequence segment encoding said (poly)peptide comprising or consisting of a cell membrane-binding domain; (c) a third sequence segment encoding a linker; and (d) a fourth sequence segment encoding said VSV-G. Further, the invention relates to a vector comprising the nucleic acid molecule of the invention, a host cell comprising said vector or nucleic acid molecule, the polypeptide encoded by said nucleic acid molecule and a method of producing the polypeptide encoded by said nucleic acid molecule. In addition, the invention relates to a pseudotyped lentiviral vector particle, a method of transducing a cell as well as a kit comprising various combinations of the nucleic acid molecule, vectors, polypeptides and host cells of the invention.

The invention is directed to a system comprising a lentivirus vector particle which encodes at least one guide RNA sequence that is complementary to a first DNA sequence in a host cell genome, a Cas9 protein, and optionally a donor nucleic acid molecule comprising a second DNA sequence. The invention also is directed to a method of altering a DNA sequence in a host cell using such a system, where the host cell can be in a human and the altered DNA can be of the human -globin gene. The invention also is directed to a fusion protein comprising a Cas9 protein and a cyclophilin A (CypA) protein. The invention also is directed to sequences of vectors that can be used in the system and method.