Chronic immune activation in HIV-1 infection contributes to reduced interferon alpha production via enhanced CD40:CD40 ligand interaction

Although a signature of increased interferon (IFN-)alpha production is observed in HIV-1 infection, the response of circulating plasmacytoid dendritic cells (PDC) to Toll-like receptor ligand stimulation is substantially impaired. This functional PDC deficit, which we specifically observed in HIV-1 infected individuals with less than 500 CD4+ T cells/µl, is not well understood. We provide evidence that the peripheral IFN-alpha production in HIV-1 infection is actively suppressed by the enhanced interaction of CD40 ligand (CD40L), a member of the tumor necrosis factor family, and its receptor CD40, which are both upregulated upon immune activation. Plasma levels of soluble CD40L were significantly higher in untreated HIV-1 infected individuals (n = 52) than in subjects on long-term antiretroviral therapy (n = 62, p<0.03) and in uninfected control donors (n = 16, p<0.001). Concomitantly, cell-associated CD40L and the expression of the receptor CD40 on the PDC were significantly upregulated in HIV-1 infection (p<0.05). Soluble and cell-associated CD40L inhibited the PDC-derived IFN-alpha production by CpG oligodeoxynucleotides dose-dependently. This suppressive effect was observed at much lower, physiological CD40L concentrations in peripheral blood mononuclear cells (PBMC) of HIV-1 infected individuals compared to controls (p<0.05). The CpG-induced IFN-alpha production in PBMC of HIV-1 infected donors was directly correlated with PDC and CD4+ T cell counts, and inversely correlated with the viral loads (p<0.001). In HIV-1 infected donors with less than 500 CD4+ T cells/µl, the CpG-induced IFN-alpha production was significantly correlated with the percentage of CD40-expressing PDC and the level of CD40 expression on these cells (p<0.05), whereas CD40L plasma levels played a minor role. In addition, low-dose CD40L contributed to the enhanced production of interleukin 6 and 8 in PBMC of HIV-1 infected donors compared to controls. Our data support the conclusion that the chronic immune activation in HIV-1 infection impairs peripheral PDC innate immune responses at least in part via enhanced CD40:CD40L interactions.     

PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function

Background

Platelet-derived chemokines are implicated in several aspects of vascular biology. However, for the chemokine platelet factor 4 variant (PF-4var/CXCL4L1), released by platelets during thrombosis and with different properties as compared to PF-4/CXCL4, its role in heart disease is not yet studied. We evaluated the determinants and prognostic value of the platelet-derived chemokines PF-4var, PF-4 and RANTES/CCL5 in patients with stable coronary artery disease (CAD).

Methodology/Principal Findings

From 205 consecutive patients with stable CAD and preserved left ventricular (LV) function, blood samples were taken at inclusion and were analyzed for PF-4var, RANTES, platelet factor-4 and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were followed (median follow-up 2.5 years) for the combined endpoint of cardiac death, non-fatal acute myocardial infarction, stroke or hospitalization for heart failure. Independent determinants of PF-4var levels (median 10 ng/ml; interquartile range 8–16 ng/ml) were age, gender and circulating platelet number. Patients who experienced cardiac events (n = 20) during follow-up showed lower levels of PF-4var (8.5 [5.3–10] ng/ml versus 12 [8–16] ng/ml, p = 0.033). ROC analysis for events showed an area under the curve (AUC) of 0.82 (95% CI 0.73–0.90, p<0.001) for higher NT-proBNP levels and an AUC of 0.32 (95% CI 0.19–0.45, p = 0.009) for lower PF-4var levels. Cox proportional hazard analysis showed that PF-4var has an independent prognostic value on top of NT-proBNP.

Conclusions

We conclude that low PF-4var/CXCL4L1 levels are associated with a poor outcome in patients with stable CAD and preserved LV function. This prognostic value is independent of NT-proBNP levels, suggesting that both neurohormonal and platelet-related factors determine outcome in these patients.     

Evolution of eye morphology and rhodopsin expression in the Drosophila melanogaster species subgroup

A striking diversity of compound eye size and shape has evolved among insects. The number of ommatidia and their size are major determinants of the visual sensitivity and acuity of the compound eye. Each ommatidium is composed of eight photoreceptor cells that facilitate the discrimination of different colours via the expression of various light sensitive Rhodopsin proteins. It follows that variation in eye size, shape, and opsin composition is likely to directly influence vision. We analyzed variation in these three traits in D. melanogaster, D. simulans and D. mauritiana. We show that D. mauritiana generally has larger eyes than its sibling species, which is due to a combination of larger ommatidia and more ommatidia. In addition, intra- and inter-specific differences in eye size among D. simulans and D. melanogaster strains are mainly caused by variation in ommatidia number. By applying a geometric morphometrics approach to assess whether the formation of larger eyes influences other parts of the head capsule, we found that an increase in eye size is associated with a reduction in the adjacent face cuticle. Our shape analysis also demonstrates that D. mauritiana eyes are specifically enlarged in the dorsal region. Intriguingly, this dorsal enlargement is associated with enhanced expression of rhodopsin 3 in D. mauritiana. In summary, our data suggests that the morphology and functional properties of the compound eyes vary considerably within and among these closely related Drosophila species and may be part of coordinated morphological changes affecting the head capsule.     

Bile acids specifically increase hepatitis C virus RNA-replication

Background

Hepatitis C virus (HCV) patients with high serum levels of bile acids (BAs) respond poorly to IFN therapy. BAs have been shown to increase RNA-replication of genotype 1 but not genotype 2a replicons. Since BAs modulate lipid metabolism including lipoprotein secretion and as HCV depends on lipids and lipoproteins during RNA-replication, virus production and cell entry, BAs may affect multiple steps of the HCV life cycle. Therefore, we analyzed the influence of BAs on individual steps of virus replication.

Methods

We measured replication of subgenomic genotype (GT) 1b and 2a RNAs as well as full-length GT2a genomes in the presence of BAs using quantitative RT-PCR and luciferase assays. Cell entry was determined using HCV pseudoparticles (HCVpp). Virus assembly and release were quantified using a core-specific ELISA. Replicon chimeras were employed to characterize genotype-specific modulation of HCV by BAs. Lunet CD81/GFP-NLS-MAVS cells were used to determine infection of Con1 particles.

Results

BAs increased RNA-replication of GT1b replicons up to 10-fold but had no effect on subgenomic GT2a replicons both in Huh-7 and HuH6 cells. They did not increase viral RNA translation, virus assembly and release or cell entry. Lowering replication efficiency of GT2a replicons rendered them susceptible to stimulation by BAs. Moreover, replication of full length GT1b with or without replication enhancing mutations and GT2a genomes were also stimulated by BAs.

Conclusions

Bile acids specifically enhance RNA-replication. This is not limited to GT1, but also holds true for GT2a full length genomes and subgenomic replicons with low replication capacity. The increase of HCV replication by BAs may influence the efficacy of antiviral treatment in vivo and may improve replication of primary HCV genomes in cell culture.     

When noisy neighbors are a blessing: analysis of gene expression noise identifies coregulated genes

In this issue of Molecular Cell, Stewart-Ornstein et?al. (2012) use systematic pair-wise correlation analysis of expression noise in a large number of yeast genes to identify clusters of functionally related genes and signaling pathways responsible for elevated noise.     

Reproductive seasonality in captive wild ruminants: implications for biogeographical adaptation,photoperiodic control,and life history

Many ruminant species show seasonal patterns of reproduction. Causes for this are widely debated, and include adaptations to seasonal availability of resources (with cues either from body condition in more tropical, or from photoperiodism in higher latitude habitats) and/or defence strategies against predators. Conclusions so far are limited to datasets with less than 30 species. Here, we use a dataset on 110 wild ruminant species kept in captivity in temperate‐zone zoos to describe their reproductive patterns quantitatively [determining the birth peak breadth (BPB) as the number of days in which 80% of all births occur]; then we link this pattern to various biological characteristics [latitude of origin, mother‐young‐relationship (hider/follower), proportion of grass in the natural diet (grazer/browser), sexual size dimorphism/mating system], and compare it with reports for free‐ranging animals. When comparing taxonomic subgroups, variance in BPB is highly correlated to the minimum, but not the maximum BPB, suggesting that a high BPB (i.e. an aseasonal reproductive pattern) is the plesiomorphic character in ruminants. Globally, latitude of natural origin is highly correlated to the BPB observed in captivity, supporting an overruling impact of photoperiodism on ruminant reproduction. Feeding type has no additional influence; the hider/follower dichotomy, associated with the anti‐predator strategy of ‘swamping’, has additional influence in the subset of African species only. Sexual size dimorphism and mating system are marginally associated with the BPB, potentially indicating a facilitation of polygamy under seasonal conditions. The difference in the calculated Julian date of conception between captive populations and that reported for free‐ranging ones corresponds to the one expected if absolute day length was the main trigger in highly seasonal species: calculated day length at the time of conception between free‐ranging and captive populations followed a y = x relationship. Only 11 species (all originating from lower latitudes) were considered to change their reproductive pattern distinctively between the wild and captivity, with 10 becoming less seasonal (but not aseasonal) in human care, indicating that seasonality observed in the wild was partly resource‐associated. Only one species (Antidorcas marsupialis) became more seasonal in captivity, presumably because resource availability in the wild overrules the innate photoperiodic response. Reproductive seasonality explains additional variance in the body mass–gestation period relationship, with more seasonal species having shorter gestation periods for their body size. We conclude that photoperiodism, and in particular absolute day length, are genetically fixed triggers for reproduction that may be malleable to some extent by body condition, and that plasticity in gestation length is an important facilitator that may partly explain the success of ruminant radiation to high latitudes. Evidence for an anti‐predator strategy involving seasonal reproduction is limited to African species. Reproductive seasonality following rainfall patterns may not be an adaptation to give birth in periods of high resource availability but an adaptation to allow conception only at times of good body condition.