No abstract

The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a longterm asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1. Here, we show that the CXC chemokine CXCL4 (PF-4), the most abundant protein contained within the α-granules of platelets, is a broad-spectrum inhibitor of HIV-1 infection. Unlike other known HIV-suppressive chemokines, CXCL4 inhibits infection by the majority of primary HIV-1 isolates regardless of their coreceptor-usage phenotype or genetic subtype. Consistent with the lack of viral phenotype specificity, blockade of HIV- 1 infection occurs at the level of virus attachment and entry via a unique mechanism that involves direct interaction of CXCL4 with the major viral envelope glycoprotein, gp120. The binding site for CXCL4 was mapped to a region of the gp120 outer domain proximal to the CD4-binding site. The identification of a platelet-derived chemokine as an endogenous antiviral factor may have relevance for the pathogenesis and treatment of HIV-1 infection

No abstract

Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, causes dominantly-inherited muscle weakness, defects of cardiac conduction, variable LV dysfunction, and risk of sudden death. The genetic basis is an expanded CTG repeat in the 3’ untranslated region of DMPK. DM1 patients are functionally hemizygous for DMPK protein, due to nuclear retention of mRNA having expanded repeats. The cardiac aspects are attributed to DMPK loss, toxicity of RNA with expanded repeats, or both. Dmpk heterozygous (+/-) and homozygous knockout (-/-) mice were reported to show AV conduction abnormalities resembling DM1 (Berul et al, JCI, 1999). In an effort to reduce RNA toxicity, antisense oligonucleotides (ASOs) targeting DMPK mRNA have recently entered clinical trials. DM1 phenotypes in skeletal muscle were corrected by ASO knockdown of toxic RNA in mice (Wheeler et al, Nature, 2012). While ASOs may have similar potential to mitigate RNA toxicity in the heart, there is risk of aggravated DMPK deficiency. To reexamine the role of DMPK in the conduction system we studied mice with Dmpk gene deletion or ASO knockdown. We obtained ECGs and echocardiograms on Dmpk -/- and +/- mice, compared to WT littermates. The +/- mice were treated with Dmpk-targeting ASOs or saline. Subcutaneous injection of 50 mg/kg/wk ASO was started at age 2 months, then shifted to biweekly injections after 6 weeks. Dmpk expression in hearts of +/- mice was ~50% of WT, and was further reduced by ASOs (84 ± 3% decrease of mRNA, 93 ± 2% decrease of protein, relative to WT). Surface ECGs and echocardiography at 6 and 10 months showed no differences of heart rate, cardiac conduction, or ejection fraction in WT, saline-treated +/-, ASO-treated +/-, or -/- mice. Conscious, unrestrained ECGs obtained at 11-12 months by radiotelemetry showed no differences among WT, saline-treated +/-, ASO-treated +/-, or -/- mice. We conclude that ASOs can induce posttranscriptional silencing of Dmpk in murine hearts. Constitutive absence of DMPK did not impact cardiac conduction or contractility, and the same was true for ASO knockdown to levels <15% of WT. Our data support the idea that cardiac dysfunction in DM1 results mainly from RNA toxicity, which potentially could be prevented or alleviated by ASOs.