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The SARS-CoV-2 B.1.1.529 variant (Omicron) contains 15 mutations on the receptor-binding domain (RBD). How Omicron would evade RBD neutralizing antibodies (NAbs) and humoral immunity requires immediate investigation. Here, we used high-throughput yeast display screening to determine the RBD escaping mutation profiles for 247 human anti-RBD NAbs identified from SARS-CoV/SARS-CoV-2 convalescents and vaccinees. Based on the results, NAbs could be unsupervised clustered into six epitope groups (A-F), which is highly concordant with knowledge-based structural classifications. Strikingly, various single mutations of Omicron could impair NAbs of different epitope groups. Specifically, NAbs in Group A-D, whose epitope overlaps with ACE2-binding motif, are largely escaped by K417N, N440K, G446S, E484A, Q493K, and G496S. Group E (S309 site) and F (CR3022 site) NAbs, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but still, a subset of NAbs are escaped by G339D, S371L, and S375F. Furthermore, B.1.1.529 pseudovirus neutralization and RBD binding assay showed that single mutation tolerating NAbs could also be escaped due to multiple synergetic mutations on their epitopes. In total, over 85% of the tested NAbs are escaped by Omicron. Regarding NAb drugs, LY-CoV016/LY-CoV555 cocktail, REGN-CoV2 cocktail, AZD1061/AZD8895 cocktail, and BRII-196 were escaped by Omicron, while VIR7831 and DXP-604 still function at reduced efficacy. Together, data suggest Omicron could cause significant humoral immune evasion, while NAbs targeting the sarbecovirus conserved region remain most effective. Our results offer instructions for developing NAb drugs and vaccines against Omicron and future variants.

The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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BackgroundMicroglia in the central nervous system (CNS) were reported to play crucial role in neurodegeneration. Previous studies showed that P2Y6 receptor (P2Y6R) mainly contributed to microglia activation and phagocytosis in CNS. However, the level of P2Y6R in Parkinson’s disease (PD) patients is unclear. Therefore, we measured the level of P2Y6R in PD patients and speculated whether it could be a potential biomarker for PD. Given on the basis that P2Y6R was higher in PD patients, we further explored the mechanisms underlying P2Y6R in the pathogenesis of PD.MethodsWe tested the expression level of P2Y6R in the peripheral blood mononuclear cells (PBMCs) among 145 PD patients, 170 healthy controls, and 30 multiple system atrophy (MSA) patients. We also used a lipopolysaccharide (LPS)-stimulated microglial cell culture model to investigate (i) the effects of LPS on P2Y6R expression with western blot and RT-PCR, (ii) the effects of LPS on UDP expression using HPLC, (iii) the effects of UDP/P2Y6R signaling on cytokine expression using western blot, RT-PCR, and ELISA, and (iv) the signaling pathways activated by the P2Y6R involved in the neuroinflammation.ResultsExpression levels of P2Y6R in PD patients were higher than healthy controls and MSA patients. P2Y6R could be a good biomarker of PD. P2Y6R was also upregulated in LPS-treated BV-2 cells and involved in proinflammatory cytokine release through an autocrine loop based on LPS-triggered UDP secretion and accelerated neuroinflammatory responses through the ERK1/2 pathway. Importantly, blocking UDP/P2Y6R signaling could reverse these pathological processes.ConclusionsP2Y6R may be a potential clinical biomarker of PD. Blocking P2Y6R may be a potential therapeutic approach to the treatment of PD patients through inhibition of microglia-activated neuroinflammation.

ObjectiveTo assess the association between Parkinson’s disease (PD) and melanoma via systematic review and meta-analysis.MethodsComprehensive search in PubMed, Web of Science, Embase and four China databases (SinoMed, WanFang data, CNKI and VIP database) of epidemiologic evidences on PD and melanoma published before April 30, 2015. Studies which reported risk estimates of melanoma among PD patients or risk estimates of PD in patients with melanoma were included. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated by random-effects models. Heterogeneity across studies was assessed using Cochran Q and I2 statistics. Subgroup analyses and sensitivity analyses were conducted to evaluate sources of heterogeneity. Subgroup analyses were done according to temporal relationship, geographic region and gender respectively. We assessed publication bias using the Begg and Egger test. In addition, study appraisal was done using a scale for observational studies to ensure the quality of evidence.ResultsWe identified 24 eligible studies on PD and melanoma with a total number of 292,275 PD patients: the pooled OR was 1.83 (95 % CI 1.46–2.30) overall, subgroup analyses by temporal relationship showed that risk of melanoma after PD diagnosis was significantly higher (OR 2.43, 95 % CI 1.77–3.32), but not before the diagnosis of PD (OR 1.09, 95 % CI 0.78–1.54). Subgroup analysis by geographic region showed that increased risk of melanoma in PD was found both in Europe (OR 1.44, 95 % CI 1.22–1.70) and in North America (OR 2.64, 95 % CI 1.63–4.28). Gender-specific subgroup analyses did not show difference between men (OR 1.64, 95 % CI 1.27–2.13) and women (OR 1.38, 95 % CI 1.04–1.82) in the risk of melanoma. In addition, we found the risk of non-melanoma skin cancers in PD was slightly higher (OR 1.20, 95 % CI 1.11–1.29) than general population. It was impossible to evaluate the association between PD and melanoma according to use of levodopa or gene polymorphism via meta-analysis since few observational or cohort studies have focused on it.ConclusionsAn association between PD and melanoma was confirmed. Most of the evidences were of high quality, and the conclusion was robust. Further research is needed to explore the mechanisms underlying this relationship.Electronic supplementary materialThe online version of this article (doi:10.1186/s40035-015-0044-y) contains supplementary material, which is available to authorized users.

Background: Pre-exposure prophylaxis (PrEP) is used as an HIV prevention method by people at substantial risk of HIV infection. This systematic review and meta-analysis evaluates current clinical evidence for use of oral TDF-based PrEP among men who have sex with men.Methods: A comprehensive literature search in PubMed, web of science, Google Scholar and ClinicalTrials.gov was performed. A random-effects meta-analysis was conducted using the event rate (ER) for estimation of the incidence of HIV and grade 3 or 4 adverse events (AE) among PrEP arm and using risk ratio (RR) for comparison of incidence of HIV and grade 3 or 4 AE between PrEP recipients and PrEP non-users. Blood-based adherence levels were also divided into three categories with reference to previous meta-analysis. Subgroup meta-analysis was also performed to evaluate whether blood-based adherence levels moderated the effect of TDF-based PrEP on HIV incidence. Narrative review was used due to inconsistent measurements of risk behavior and drug resistance. This review is registered on the PROSPERO database (CRD42017077965).Results: Fourteen studies were included in the review. Oral TDF-based PrEP significantly reduced HIV incidence with minimum drug resistance and tolerable safety risks (HIV incidence, ER = 1.1%, 95% CI 0.6–2.0%, p < 0.001, RR = 0.244, 95% CI 0.111–0.537, p < 0.001 and grade 3 or 4 AEs, ER = 13.0%, 95% CI 9.9–16.9%, p < 0.001, RR = 1.059, 95% CI 0.824–1.362, p = 0.653). Oral TDF-based PrEP was more effective in reducing HIV incidence with high levels of blood-based PrEP adherence (ER, 0.4%) compared to moderate adherence (2.9%; p < 0.001). Most studies found no association between PrEP use and self-reported sexual behavior.Conclusion: Oral TDF-based PrEP is an effective intervention to prevent against HIV infection among MSM. Well-designed implementation science studies that integrate sociobehavioral and biomedical interventions are needed to identify optimal PrEP delivery models in different populations to translate biomedical efficacy into real-world efficacy.

Emerging evidence suggests that the microbiota present in feces plays a role in Parkinson’s disease (PD). However, the alterations of the microbiome in the blood of PD patients remain unknown. To test this hypothesis, we conducted this case-control study to explore the microbiota compositions in the blood of Chinese PD patients. Microbiota communities in the blood of 45 patients and their healthy spouses were investigated using high-throughput Illumina HiSeq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene. The relationships between the microbiota in the blood and PD clinical characteristics were analyzed. No difference was detected in the structure and richness between PD patients and healthy controls. The following genera were enriched in the blood of PD patients: Isoptericola, Cloacibacterium, Enhydrobacter and Microbacterium; whereas genus Limnobacter was enriched in the healthy controls after adjusting for age, gender, body mass index (BMI) and constipation. Additionally, the findings regarding these genera were validated in another independent group of 58 PD patients and 57 healthy controls using real-time PCR targeting genus-specific 16S rRNA genes. Furthermore, not only the genera Cloacibacterium and Isoptericola (which were identified as enriched in PD patients) but also the genera Paludibacter and Saccharofermentans were positively associated with disease duration. Some specific genera in the blood were related to mood disorders. We believe this is the first report to provide direct evidence to support the hypothesis that the identified microbiota in the blood are associated with PD. Additionally, some microbiota in the blood are closely associated with the clinical characteristics of PD. Elucidating these differences in blood microbiomes will provide a foundation to improve our understanding of the role of microbiota in the pathogenesis of PD.