No association of a risk variant for severe COVID-19 with HIV protection in three cohorts of highly exposed individuals.

An extended haplotype on chromosome 3 is the major genetic risk factor for severe COVID-19. The risk haplotype, which was inherited from Neanderthals, decreases the expression of several cytokine receptors, including CCR5. Recently, a study based on three general population cohorts indicated that the minor allele of one of the variants in the haplotype (rs17713054) protects against HIV infection. We thus expected this allele to be over-represented in highly exposed individuals who remain uninfected (exposed seronegative individuals, ESN). To perform a meta-analysis, we genotyped rs17713054 in three ESN cohorts of European ancestry exposed to HIV through different routes. No evidence of association was detected in the single cohorts. The meta-analysis also failed to detect any effect of the variant on protection from HIV-1. The same results were obtained in a Cox-regression analysis for the time to seroconversion. An in-vitro infection assay did not detect differences in viral replication as a function of rs17713054 genotype status. We conclude that the rs17713054 minor allele is not associated with the ESN phenotype and does not modulate HIV infection in vitro.

MiR-195 enhances cardiomyogenic differentiation of the proepicardium/septum transversum by Smurf1 and Foxp1 modulation.

Cardiovascular development is a complex developmental process in which multiple cell lineages are involved, namely the deployment of first and second heart fields. Beside the contribution of these cardiogenic fields, extracardiac inputs to the developing heart are provided by the migrating cardiac neural crest cells and the proepicardial derived cells. The proepicardium (PE) is a transitory cauliflower-like structure located between the cardiac and hepatic primordia. The PE is constituted by an internal mesenchymal component surrounded by an external epithelial lining. With development, cells derived from the proepicardium migrate to the neighboring embryonic heart and progressive cover the most external surface, leading to the formation of the embryonic epicardium. Experimental evidence in chicken have nicely demonstrated that epicardial derived cells can distinctly contribute to fibroblasts, endothelial and smooth muscle cells. Surprisingly, isolation of the developing PE anlage and ex vivo culturing spontaneously lead to differentiation into beating cardiomyocytes, a process that is enhanced by Bmp but halted by Fgf administration. In this study we provide a comprehensive characterization of the developmental expression profile of multiple microRNAs during epicardial development in chicken. Subsequently, we identified that miR-125, miR-146, miR-195 and miR-223 selectively enhance cardiomyogenesis both in the PE/ST explants as well as in the embryonic epicardium, a Smurf1- and Foxp1-driven process. In addition we identified three novel long non-coding RNAs with enhanced expression in the PE/ST, that are complementary regulated by Bmp and Fgf administration and well as by microRNAs that selectively promote cardiomyogenesis, supporting a pivotal role of these long non coding RNAs in microRNA-mediated cardiomyogenesis of the PE/ST cells.

Association of complement C3d receptor 2 genotypes with the acquisition of HIV infection in a trial of recombinant glycoprotein 120 vaccine.

OBJECTIVES: Complement C3d receptor 2 (CR2) is the main receptor for complement protein C3d and plays an important role in adaptive immune responses. CR2 genetic variants are associated with susceptibility to systemic lupus erythematosus as well as to HIV-1 infection. In addition, CR2 function can be subverted by HIV-1 for an efficient entry into target cells; in a process known as antibody-dependent enhancement of viral infection. We sought to determine the association between CR2 gene variants with HIV-1 acquisition after vaccination with recombinant gp120 protein (Vax004 clinical trial). DESIGN AND METHODS: This is a retrospective cross-sectional study, comprising male volunteers of European ancestry including infected (n = 273) and uninfected (n = 402) vaccinees and placebo, who were genotyped for three single nucleotide polymorphisms (SNPs) in the CR2 gene region. RESULTS: An interaction was observed between the baseline sexual behavior and the SNP rs3813946 for higher risk of infection in vacinees (interaction term P = 0.02). This SNP was associated with increased susceptibility to HIV-1 infection after vaccination in volunteers with low behavioral risk odds ratio (95% confidence interval): 5.5 (1.4-21.7) P = 0.006 but not vaccinees with high behavioral risk or volunteers given placebo (P = 0.7). Moreover, CR2 genotype was strongly associated with the rate of HIV-1 acquisition after vaccination in low-risk volunteers [hazard odds ratio (95% confidence interval): 3.3 (1.6-7.0), P = 0.001]. CONCLUSION: The current study suggests that CR2 may play a role in HIV-1 acquisition after vaccination with rgp120 proteins.

The Role of Non-Coding RNA in Congenital Heart Diseases.

Cardiovascular development is a complex developmental process starting with the formation of an early straight heart tube, followed by a rightward looping and the configuration of atrial and ventricular chambers. The subsequent step allows the separation of these cardiac chambers leading to the formation of a four-chambered organ. Impairment in any of these developmental processes invariably leads to cardiac defects. Importantly, our understanding of the developmental defects causing cardiac congenital heart diseases has largely increased over the last decades. The advent of the molecular era allowed to bridge morphogenetic with genetic defects and therefore our current understanding of the transcriptional regulation of cardiac morphogenesis has enormously increased. Moreover, the impact of environmental agents to genetic cascades has been demonstrated as well as of novel genomic mechanisms modulating gene regulation such as post-transcriptional regulatory mechanisms. Among post-transcriptional regulatory mechanisms, non-coding RNAs, including therein microRNAs and lncRNAs, are emerging to play pivotal roles. In this review, we summarize current knowledge on the functional role of non-coding RNAs in distinct congenital heart diseases, with particular emphasis on microRNAs and long non-coding RNAs.