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PLoS Pathog. 2019 Aug 29;15(8):e1007958. doi: 10.1371/journal.ppat.1007958. eCollection 2019 Aug.

The mutation of Transportin 3 gene that causes limb girdle muscular dystrophy 1F induces protection against HIV-1 infection.

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AIDS Immunopathogenesis Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium.
Department of Infectious Diseases, Hospital Ramón y Cajal, Alcalá de Henares University, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Laboratory for Photochemistry and Spectroscopy, Molecular Imaging and Photonics, Department of Chemistry, KU Leuven, Flanders, Belgium.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.
Infectious Diseases Unit, IBIDAPS, Hospital Clínic, University of Barcelona, Spain.


The causative mutation responsible for limb girdle muscular dystrophy 1F (LGMD1F) is one heterozygous single nucleotide deletion in the stop codon of the nuclear import factor Transportin 3 gene (TNPO3). This mutation causes a carboxy-terminal extension of 15 amino acids, producing a protein of unknown function (TNPO3_mut) that is co-expressed with wild-type TNPO3 (TNPO3_wt). TNPO3 has been involved in the nuclear transport of serine/arginine-rich proteins such as splicing factors and also in HIV-1 infection through interaction with the viral integrase and capsid. We analyzed the effect of TNPO3_mut on HIV-1 infection using PBMCs from patients with LGMD1F infected ex vivo. HIV-1 infection was drastically impaired in these cells and viral integration was reduced 16-fold. No significant effects on viral reverse transcription and episomal 2-LTR circles were observed suggesting that the integration of HIV-1 genome was restricted. This is the second genetic defect described after CCR5Δ32 that shows strong resistance against HIV-1 infection.

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