The human
TRIM5
genes encodes a retroviral restriction factor (TRIM5α). Evolutionary analyses of this gene in mammals have revealed a complex and multifaceted scenario, suggesting that
TRIM5
has been ...the target of exceptionally strong selective pressures, possibly exerted by recurrent waves of retroviral infections.
TRIM5
displays inter-individual expression variability in humans and high levels of
TRIM5
mRNA have been associated with a reduced risk of HIV-1 infection. We resequenced
TRIM5
in chimpanzees and identified two polymorphisms in intron 1 that are shared with humans. Analysis of the gene region encompassing the two
trans
-specific variants in human populations identified exceptional nucleotide diversity levels and an excess of polymorphism compared to fixed divergence. Most tests rejected the null hypothesis of neutral evolution for this region and haplotype analysis revealed the presence of two deeply separated clades. Calculation of the time to the most recent common ancestor (TMRCA) for
TRIM5
haplotypes yielded estimates ranging between 4 and 7 million years. Overall, these data indicate that long-term balancing selection, an extremely rare process outside MHC genes, has maintained
trans
-specific polymorphisms in the first intron of
TRIM5.
Bioinformatic analyses indicated that variants in intron 1 may affect transcription factor-binding sites and, therefore,
TRIM5
transcriptional activity. Data herein confirm an extremely complex evolutionary history of
TRIM5
genes in primates and open the possibility that regulatory variants in the gene modulate the susceptibility to HIV-1.
HIV-1 induces activation of complement through the classical and lectin pathways. However, the virus incorporates several membrane-bound or soluble regulators of complement activation (RCA) that ...inactivate complement. HIV-1 can also use the complement receptors (CRs) for complement-mediated antibody-dependent enhancement of infection (Ć-ADE). We hypothesize that hypofunctional polymorphisms in RCA or CRs may protect from HIV-1 infection. For this purpose, 139 SNPs located in 19 RCA and CRs genes were genotyped in a population of 201 Spanish HIV-1-exposed seronegative individuals (HESN) and 250 HIV-1-infected patients. Two SNPs were associated with infection susceptibility, rs1567190 in CR2 (odds ratio (OR) = 2.27, P = 1 × 10(-4)) and rs2842704 in C4BPA (OR = 2.11, P = 2 × 10(-4)). To replicate this finding, we analyzed a cohort of Italian, sexually HESN individuals. Although not significant (P = 0.25, OR = 1.57), similar genotypic proportions were obtained for the CR2 marker rs1567190. The results of the two association analyses were combined through a random effect meta-analysis, with a significant P-value of 2.6 x 10(-5) (OR = 2.07). Furthermore, we found that the protective CR2 genotype is correlated with lower levels CR2 mRNA as well as differences in the ratio of the long and short CR2 isoforms.
Acute respiratory tract infections (ARTIs) are the most frequent illnesses in pediatric age, frequently experienced in children with Down Syndrome (DS) due to the associated immune defects of both ...specific and non-specific immunity. Pidotimod, a synthetic immunostimulant, was shown to reduce the rates of ARTIs in children with DS, however the mechanisms associated with this effect is currently unknown. We analyzed immune parameters in DS children who received the seasonal 20112012 virosomal-adjuvanted influenza vaccine. Eighteen children aged 3-10 years (mean age 7.1+/-2.6 years) were randomly assigned (1:1 ratio) to receive Pidotimod 400 mg, administered orally once a day for 90 days or placebo. At the recruitment (T0) all children received a single dose of virosomal-adjuvanted influenza vaccine (Flu). Blood samples were collected at T0 and 3 months after the recruitment (T3) in order to evaluate innate and adaptative immune responses pathway. Flu-specific IgG1 and IgG3 levels in plasma samples were determined at pre-vaccination (T0), and 1 (T1) and 3 months (T3) post-vaccination. The use of Pidotimod was associated with the upregulation of a number of genes involved in the activation of innate immune responses and in antimicrobial activity. Interestingly the ratio of Flu-specific IgG1/IgG3 was skewed in pidotimod-treated individuals, suggesting a preferential activation of complement-dependent effector mechanisms. Although preliminary these data suggest that Pidotimod can potentiate the beneficial effect of immunization, possibly resulting in a stronger activity of both innate and adaptive immune responses.
SARS-CoV-2 transmission mainly occurs through exposure of the upper airway mucosa to infected secretions such as saliva, which are excreted by an infected person. Thus, oral mucosal immunity plays a ...central role in the prevention of and early defense against SARS-CoV-2 infection. Although virus-specific antibody response has been extensively investigated in blood samples of SARS-CoV-2-infected patients and vaccinees, local humoral immunity in the oral cavity and its relationship to systemic antibody levels needs to be further addressed.
We fine-tuned a virus neutralization assay (vNTA) to measure the neutralizing activity (NA) of plasma and saliva samples from 20 SARS-CoV-2-infected (SI), 40 SARS-CoV-2-vaccinated (SV), and 28 SARS-CoV-2-vaccinated subjects with a history of infection (SIV) using the "wild type" SARS-CoV-2 lineage B.1 (EU) and the Delta (B.1.617.2) strains. To validate the vNTA results, the presence of neutralizing antibodies (NAbs) to the spike receptor binding domain (RBD) was evaluated with an ELISA assay.
NA to SARS-CoV-2 lineage B.1 (EU) was present in plasma samples from all the tested subjects, with higher titers in SIV compared to both SI and SV. Conversely, NA was detected in saliva samples from 10.3% SV, 45% SI, and 92.6% SIV, with significantly lower titers in SV compared to both SI and SIV. The detection of NAbs in saliva reflected its reduced NA in SV.
The difference in NA of plasma vs. saliva was confirmed in a vNTA where the SARS-CoV-2 B.1 and Delta strains were tested head-to-head, which also revealed a reduced NA of both specimens compared to the B.1 variant.
The administration of SARS-CoV-2 vaccines was associated with limited virus NA in the oral cavity, as measured in saliva and in comparison to plasma. This difference was more evident in vaccinees without a history of SARS-CoV-2 infection, possibly highlighting the importance of local exposure at the site of virus acquisition to effectively prevent the infection and block its spread. Nevertheless, the presence of immune escape mutations as possibly represented by the SARS-CoV-2 Delta variant negatively affects both local and systemic efficacy of NA associated with vaccination.
A 29-year-old man was observed to develop insulin-dependent diabetes mellitus following a 5-month treatment with recombinant α-2b-interferon for chronic hepatitis C. After the onset of the disease, ...serum samples that had, respectively, been collected before therapy commencement, at month 3, and at the onset of insulin-dependent diabetes mellitus were tested for islet-cell (ICA-IgG), glutamic acid decarboxylase (GAD-Abs), IA2 (IA2-Abs) and insulin (IA-Abs) autoantibodies. The following results were obtained: ICA-IgG, 5, > 80, and > 80 JDF-U, respectively; GAD-Abs: > 100 U/ml in all three measurements; IA2-Abs and IA-Abs: negative. During treatment, thyroid microsomal autoantibodies increased markedly (from 1:100 to 25 600 titer); thyroid-stimulating hormone was persistently normal. HLA class II typing revealed a genetic predisposition to insulin-dependent diabetes mellitus as demonstrated by the presence of DRBI*
04
08
, DQ A1 52 Arg+/Arg+, and DQB1 57 N-Asp/Asp alleles. One year after the onset of insulin-dependent diabetes mellitus, the patient is still receiving 30 IU insulin daily; the liver function tests are normal and HCV-RNA is negative. These data support the hypothesis that, in predisposed patients, α-interferon therapy can enhance an ongoing autoimmune process against pancreatic β-cells and induce overt insulin-dependent diabetes mellitus. We therefore suggest that, in patients with a documented predisposition to insulin-dependent diabetes mellitus, α-IFN therapy should be administered with caution.
With increasing interest around social impact investments, there is a pressing need to properly define the universe of social impact targets. This paper aims to identify communities of social impact ...firms (SIFs) ranked in terms of their compliance with the OECD criteria for impact investing. We include in the analysis the network dimension of the firms. Specifically, we assume that SIFs represent the nodes of a weighted complex network, whose weights grow when the linked nodes show similar behaviors in pursuing social impact targets. To empirically validate our model, we used a novel hand-collected dataset of SIFs across multiple countries. Our results highlight that the economic sector and country of origin do not act as a distinguishing factor among SIF communities. However, firm size seems to matter as firms which are more compliant with the social impact criteria tend to be smaller.
Human ERAP1 and ERAP2 encode two endoplasmic reticulum aminopeptidases. These enzymes trim peptides to optimal size for loading onto major histocompatibility complex class I molecules and shape the ...antigenic repertoire presented to CD8+ T cells. Therefore, ERAP1 and ERAP2 may be considered potential selection targets and modulators of infection susceptibility. We resequenced two genic regions in ERAP1 and ERAP2 in three HapMap populations. In both cases, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and reduced population genetic differentiation. The genealogy of ERAP1 and ERAP2 haplotypes was split into two major branches with deep coalescence times. These features suggest that long-standing balancing selection has acted on these genes. Analysis of the Lys528Arg (rs30187 in ERAP1) and Asn392Lys (rs2549782 in ERAP2) variants in an Italian population of HIV-1-exposed seronegative (ESN) individuals and a larger number of Italian controls indicated that rs2549782 significantly deviates from Hardy–Weinberg equilibrium (HWE) in ESN but not in controls. Technical errors were excluded and a goodness-of-fit test indicated that a recessive model with only genetic effects adequately explains HWE deviation. The genotype distribution of rs2549782 is significantly different in the two cohorts (P = 0.004), mainly as the result of an over-representation of Lys/Lys genotypes in the ESN sample (P-value for a recessive model: 0.00097). Our data suggest that genetic diversity in ERAP1 and ERAP2 has been maintained by balancing selection and that variants in ERAP2 confer resistance to HIV-1 infection possibly via the presentation of a distinctive peptide repertoire to CD8+ T cells.
HIV-infected patients have a greater burden of sub-clinical and clinical atherosclerotic disease compared to the general population. The primary objective of this study was to compare the relative ...roles of inflammation, endothelial alterations, and metabolic factors in the induction and maintenance of atherosclerosis in antiretroviral therapy (ART)-treated or ART-naive patients.
Cross-sectional study; 79 HIV-infected patients (55 ART-treated and 24 naive individuals) were consecutively enrolled. In both groups, nearly 50% of the individuals had a high cardiovascular risk (Framingham value >20%).
Echo-Doppler intima-media thickness (IMT), inflammatory, thrombophilic, endothelial, metabolic indexes, and cholesterol efflux molecules were evaluated. Multivariate analysis adjusted for age, CD4 nadir, BMI, and Framingham's score were used to analyze the results.
A complex pathogenesis drives atherogenesis in HIV infection. Thus, whereas inflammation could be responsible for this process in ART-naive individuals, metabolic factors low-density lipoprotein (LDL), apolipoprotein B (ApoB), lipoprotein A seem to play a more prevalent role in ART-treated patients. Notably, ABCA-1, an ATP-binding transporter cassette protein involved in cholesterol efflux, which is inhibited by Nef, is up-regulated in ART-treated individuals.
Atherosclerosis in HIV infection results from the interaction of multiple factors: an inflammatory and HIV-driven disease could prevail in the absence of therapy; metabolic, non-inflammatory causes may be more important in patients undergoing therapy. Approaches to atherosclerotic disease in HIV infection should consider these differences.
Dendritic cell-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) participates in the initial stages of sexually transmitted HIV-1 infection by recognizing highly ...mannosylated structures presented in multiple copies on HIV-1 gp120 and promoting virus dissemination. Inhibition of HIV interaction with DC-SIGN thus represents a potential therapeutic approach for viral entry inhibition at the mucosal level.
Herein we evaluate the efficacy in inhibiting HIV-1 infection and the potential toxicity of a multimeric glycomimetic DC-SIGN ligand (Dendron 12).
The ability of Dendron 12 to block HIV-1 infection was assessed in cellular and human cervical explant models. Selectivity of Dendron 12 towards DC-SIGN and langerin was evaluated by surface plasmon resonance studies. β chemokine production following stimulation with Dendron 12 was also analyzed. Toxicity of the compound was evaluated in cellular and tissue models.
Dendron 12 averted HIV-1 trans infection of CD4(+) T lymphocytes in presence of elevated viral loads and prevented HIV-1 infection of human cervical tissues, under conditions mimicking compromised epithelial integrity, by multiple clades of R5 and X4 tropic viruses. Treatment with Dendron 12 did not interfere with the activity of langerin and also significantly elicited the production of the β chemokines MIP-1α, MIP-1β and RANTES.
Dendron 12 thus inhibits HIV-1 infection by competition with binding of HIV to DC-SIGN and stimulation of β-chemokine production. Dendron 12 represents a promising lead compound for the development of anti-HIV topical microbicides.
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