Genetic Correction of Dystrophin Deficiency and Skeletal Muscle Remodeling in Adult MDX Mouse via Transplantation of Retroviral Producer Cells

Duchenne muscular dystrophy (DMD) is an X-linked, lethal disease caused by mutations of the dystrophin gene. No effective therapy is available, but dystrophin gene transfer to skeletal muscle has been proposed as a treatment for DMD. We have developed a strategy for efficient in vivo gene transfer of dystrophin cDNA into regenerating skeletal muscle. Retroviral producer cells, which release a vector carrying the therapeutically active dystrophin minigene, were mitotically inactivated and transplanted in adult nude/ mdx mice. Transplantation of 3 3 10 6 producer cells in a single site of the tibialis anterior muscle resulted in the transduction of between 5.5 and 18% total muscle fibers. The same procedure proved also feasible in immunocompetent mdx mice under short-term pharmacological immunosuppression. Minidystrophin expression was stable for up to 6 mo and led to a -sarcoglycan reexpression. Muscle stem cells could be transduced in vivo using this procedure. Transduced dystrophic skeletal muscle showed evidence of active remodeling reminiscent of the genetic normalization process which takes place in female DMD carriers. Overall, these results demonstrate that retroviral-mediated dystrophin gene transfer via transplantation of producer cells is a valid approach towards the long-term goal of gene therapy of DMD. ( J. Clin. Invest. 1997. 100:620–628 .

Monsef Benkirane awarded 2013 Ming K. Jeang Foundation Retrovirology Prize: landmark HIV-1 research honoured.

AbstractDr. Monsef Benkirane, from the Laboratoire de Virologie Moleculaire in Montpellier, France, has been announced as the recipient of the 2013 Retrovirology Prize. This bi-annual prize covers all aspects of the Retrovirology field and celebrates groundbreaking research from retrovirologists aged between 45 and 60. Monsef is among the brightest young "stars" in HIV-1 biology. At 45 years of age, he is the youngest recipient of the Retrovirology prize. This year the competition was particularly fierce with 4 strong contenders.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

HIV-1 exploits importin 7 to maximize nuclear import of its DNA genome

<p>Abstract</p> <p>Background</p> <p>Nuclear import of the HIV-1 reverse transcription complex (RTC) is critical for infection of non dividing cells, and importin 7 (imp7) has been implicated in this process. To further characterize the function of imp7 in HIV-1 replication we generated cell lines stably depleted for imp7 and used them in conjunction with infection, cellular fractionation and pull-down assays.</p> <p>Results</p> <p>Imp7 depletion impaired HIV-1 infection but did not significantly affect HIV-2, simian immunodeficiency virus (SIVmac), or equine infectious anemia virus (EIAV). The lentiviral dependence on imp7 closely correlated with binding of the respective integrase proteins to imp7. HIV-1 RTC associated with nuclei of infected cells with remarkable speed and knock down of imp7 reduced HIV-1 DNA nuclear accumulation, delaying infection. Using an HIV-1 mutant deficient for reverse transcription, we found that viral RNA accumulated within nuclei of infected cells, indicating that reverse transcription is not absolutely required for nuclear import. Depletion of imp7 impacted on HIV-1 DNA but not RNA nuclear import and also inhibited DNA transfection efficiency.</p> <p>Conclusion</p> <p>Although imp7 may not be essential for HIV-1 infection, our results suggest that imp7 facilitates nuclear trafficking of DNA and that HIV-1 exploits imp7 to maximize nuclear import of its DNA genome. Lentiviruses other than HIV-1 may have evolved to use alternative nuclear import receptors to the same end.</p

Obituary: Kuan-Teh Jeang.

Dear colleagues: Our loyal friend Kuan-Teh Jeang, "Teh" to friends and colleagues, passed away unexpectedly at the age of 54 on the evening of January 27, 2013. Great shock and sorrow was apparent in the avalanche of email messages by the very many international colleagues with whom Teh interacted over the years. Many of us came to know Teh as an energetic and gifted scientist for whom we had much respect and affection.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

From Duke to King's: Michael Malim wins the 2010 Retrovirology prize

Michael H. Malim wins the Retrovirology prize

HIV-1 capsid is involved in post-nuclear entry steps

BACKGROUND: HIV-1 capsid influences viral uncoating and nuclear import. Some capsid is detected in the nucleus but it is unclear if it has any function. We reported that the antibiotic Coumermycin-A1 (C-A1) inhibits HIV-1 integration and that a capsid mutation confers resistance to C-A1, suggesting that capsid might affect post-nuclear entry steps. RESULTS: Here we report that C-A1 inhibits HIV-1 integration in a capsid-dependent way. Using molecular docking, we identify an extended binding pocket delimited by two adjacent capsid monomers where C-A1 is predicted to bind. Isothermal titration calorimetry confirmed that C-A1 binds to hexameric capsid. Cyclosporine washout assays in Jurkat CD4+ T cells expressing engineered human TRIMCyp showed that C-A1 causes faster and greater escape from TRIMCyp restriction. Sub-cellular fractionation showed that small amounts of capsid accumulated in the nuclei of infected cells and C-A1 reduced the nuclear capsid. A105S and N74D capsid mutant viruses did not accumulate capsid in the nucleus, irrespective of C-A1 treatment. Depletion of Nup153, a nucleoporin located at the nuclear side of the nuclear pore that binds to HIV-1 capsid, made the virus less susceptible to TRIMCyp restriction, suggesting that Nup153 may help maintain some integrity of the viral core in the nucleus. Furthermore C-A1 increased binding of CPSF6, a nuclear protein, to capsid. CONCLUSIONS: Our results indicate that capsid is involved in post-nuclear entry steps preceding integration

A trip down memory lane with Retrovirology

Fifteen years ago, Retrovirology was amongst the first open-access journals to be established through Biomed Central, instigated by our late Founding Editor Dr. Kuan-Teh Jeang. Since then, in what seemed like a rather daring move to be paper-free, Retrovirology has witnessed the exponential growth of open access journals that have changed the landscape of scientific publishing and communications. As was pointed out by the staff editors in PLoS Biology [1], the infancy of open access journal was a very different time from our present day, which was before smartphones, prior to most of the digital social media platforms and at a time when we had only begun to learn about the completed DNA sequences from the Human Genome Projec