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

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.

Insight in miRNome of Long-Term Non-Progressors and Elite Controllers Exposes Potential RNAi Role in Restraining HIV-1 Infection

“…ADAM10 and TPNO3 have been suggested as targets of this miRNA, and their part in nuclear transport of the preintegration complex is of the essence for the establishment of proviral DNA [84]. Rodriguez-Mora et al showed that a defective mutation in TPNO3 confers protection against HIV infection [85]. This fact bolsters the relevance of this miRNA in the control of the virus and further research is necessary.…”

Resistance to human immunodeficiency virus infection: a rare but neglected state

“…The main causes of control of HIV viremia reported to date include allelic variants in genes encoding HIV coreceptors, such as CCR5, 14,15 CCR2, 31 and CXCR6; 32 the cell surface density of CXCR4 33 and CCR5 coreceptors; 34 mutation of the transportin 3 gene; 19 the level of expression of the CXCR4 ligand SDF‐1 35 and the CCR5 ligands RANTES and MIP‐1α; 36 HLA class I genotypes such as HLA‐B * 27, 37 HLA‐B * 57, 38 and HLA‐B * 39; 39 production of cytokines such as IL‐10; 40 cellular immune responses including anti‐p24 Gag CD4 + T cells 41 and anti‐p24 gag and anti‐Pol CD8 + T cells; 42,43 and humoral immune responses, such as anti‐gp41 env 44 and anti‐gp120 env neutralizing antibodies 45 . Restriction against HIV infection can also apply at the level of host cells (so‐called intrinsic antiviral immunity) via expression of antiviral factors including APOBEC3G, 46 TRIM5‐alpha, 47 TRIM22, 48 TRIM11, 49 tetherin/CD317, 50 SAMHD1, 51 or SERINC5; 52 RNA silencing through microRNAs such as miRNA‐1236 and miRNA‐29; 53,54 proviral long terminal repeat (LTR) silencing by methylation; 55 histone deacetylases HDAC; 56 or by histone H1‐mediated Tat repression, 57 among others (for a more comprehensive list, see Turner and Margolis 58 ).…”

“…In other words, researchers should segregate the major players in HIV restriction that lead to elite control in HESN individuals from factors that have a secondary role, even if the latter have been shown in vitro to delay or completely inhibit HIV replication. The newly described genetic HIV resistance associated with the nuclear import factor transportin 3 gene ( TNPO3 ) 19 may hopefully join this category of major factors.…”

“…CCR5‐delta32 is the most studied HIV‐resistance mechanism since the discovery of HIV. Yet, not all HIV‐resistant individuals have a CCR5‐delta 32 deletion; several other mechanisms of resistance of either genetic origin, such as the recently reported TNPO3 mutation, 19 or epigenetic modifications and/or environmental factors have been reported. Among the environmental factors, ongoing studies suggest that HIV‐infected patients and HIV‐negative healthy controls do not carry the same bacterial gut microbiota composition 20 .…”

Génétique : Une mutation du gène TNPO3 impliquée dans la LGMD D2 confère une protection à l’infection par le VIH-1

“…La dystrophie musculaire des ceintures autosomique dominante de type D2 (ou LGMD 1F d'après l'ancienne nomenclature) est causée par une mutation hétérozygote (délétion d'un nucléotide dans le codon de terminaison de la traduction) dans le gène TNPO3 codant le facteur d'import nucléaire Transportine 3 [1]. Cette mutation entraîne un allongement de la protéine de 15 acides aminés au niveau carboxy-terminal, ce qui produit la co-expression de la protéine sauvage (TNPO3_wt) et de celle mutée (TNPO3_ mut) dont la fonction est inconnue.…”