Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adolescent
-
Adult
-
Case-Control Studies
-
Child
-
Child, Preschool
-
Female
-
HIV Infections / genetics
-
HIV Infections / prevention & control*
-
HIV Infections / virology
-
HIV-1 / physiology*
-
Humans
-
Infant
-
Male
-
Middle Aged
-
Muscular Dystrophies, Limb-Girdle / genetics
-
Muscular Dystrophies, Limb-Girdle / pathology*
-
Mutation*
-
Pedigree
-
Virus Replication / genetics*
-
Young Adult
-
beta Karyopherins / genetics*
Substances
-
TNPO3 protein, human
-
beta Karyopherins
Grants and funding
This work was supported by crowfunding site PRECIPITA from FECYT, the MERCKSALUD Foundation, the Spanish Ministry of Science (FIS PI12/00969; PI16CIII/00034; SAF2016-78480-R); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (FEDER); CIBERer-ISCIII (FIS PI16/00316) co-financed by the European Regional Development Founds (FEDER), IIS La Fe (2016-0388; 2018-0200), and Fundación Isabel Gemio (
http://www.fundacionisabelgemio.com). The work of Dra. Sara Rodríguez-Mora is supported by the Asociación Conquistando Escalones, funded by Spanish LGMD1F patients and Sara Borrell grant from Instituto de Salud Carlos III. The work of Dra. María Rosa López-Huertas is financed by ISCIII-Subdirección General de Evaluación and European Funding for Regional Development (FEDER) and by Spanish Ministry of Economy and Competitiveness (PIE13/00040). The work of Elena Mateos is supported by the Spanish Ministry of Economy and Competitiveness SAF2016-78480-R. The work of Lorena Vigón is supported by a pre-doctoral grant from Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.