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NK cells and CD8 + T cells both contribute to HIV-1 control. These cells not only suppress HIV-1 replication, but also select HIV-1 escape mutant viruses. Most viruses bearing T cell escape mutations are expected to remain susceptible to NK cell suppression, but their inhibition by NK cells is unclear. We investigated the role of HIV-1-specific CD8 + T cells and NK cells recognizing superimposed Pol peptides in selection and control of HIV-1 mutant virus. KIR2DL2 + NK cells have an enhanced ability to recognize HIV-1-infected cells after selection of Pol mutant virus by PolIY11-specific HLA-C*12:02-restricted T cells. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and analysis of crystal structures of TCR- and KIR2DL2-HLA-C*12:02-peptide complexes demonstrate the molecular basis for selection and recognition of the escape mutant epitope by TCR and KIR2DL2. The present study elucidates the mechanism for selection and inhibition of an HIV-1 escape virus by T cells and NK cells. HIV replication has been shown previously to be inhibited by combinations of T cells and NK cells according to HLA and KIR haplotype. Here the authors consider a combination of KIR2DL2+ NK and HLA-C*12:02-restricted T cells and clarify how a specific HIV pol escape mutant facilitates virus control by KIR2DL2+ NK cells.

Natural killer (NK) cells play an important role in immune rejection in solid organ transplantation. To mitigate human NK cell activation in xenotransplantation, introducing inhibitory ligands on xenografts via genetic engineering of pigs may protect the graft from human NK cell-mediated cytotoxicity and ultimately improve xenograft survival. In this study, non-classical HLA class I molecules HLA-E and HLA-G were introduced in an immortalized porcine liver endothelial cell line with disruption of five genes ( GGTA1 , CMAH , β4galNT2 , SLA-I α chain , and β-2 microglobulin ) encoding three major carbohydrate xenoantigens (αGal, Neu5Gc, and Sda) and swine leukocyte antigen class I (SLA-I) molecules. Expression of HLA-E and/or HLA-G on pig cells were confirmed by flow cytometry. Endogenous HLA-G molecules as well as exogenous HLA-G VL9 peptide could dramatically enhance HLA-E expression on transfected pig cells. We found that co-expression of HLA-E and HLA-G on porcine cells led to a significant reduction in human NK cell activation compared to the cells expressing HLA-E or HLA-G alone and the parental cell line. NK cell activation was assessed by analysis of CD107a expression in CD3 - CD56 + population gated from human peripheral blood mononuclear cells. CD107a is a sensitive marker of NK cell activation and correlates with NK cell degranulation and cytotoxicity. HLA-E and/or HLA-G on pig cells did not show reactivity to human sera IgG and IgM antibodies. This in vitro study demonstrated that co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells provided a superior inhibition in human xenoreactive NK cells, which may guide further genetic engineering of pigs to prevent human NK cell mediated rejection.

Fine definition of targeted CD8+ T-cell epitopes and their human leucocyte antigen (HLA) class I restriction informs iterative improvements of HIV-1 T-cell vaccine designs and may predict early vaccine success or failure. Here, lymphocytes from volunteers, who had received candidate HIVconsv vaccines expressing conserved sub-protein regions of HIV-1, were used to define the optimum-length target epitopes and their HLA restriction. In HIV-1-positive patients, CD8+ T-cell responses predominantly recognize immunodominant, but hypervariable and therefore less protective epitopes. The less variable, more protective epitopes in conserved regions are typically subdominant. Therefore, induction of strong responses to conserved regions by vaccination provides an opportunity to discover novel important epitopes. Cryopreserved lymphocytes from vaccine recipients were expanded by stimulation with 15-mer responder peptides for 10 days to establish short term-cell-line (STCL) effector cells. These were subjected to intracellular cytokine staining using serially truncated peptides and peptide-pulsed 721.221 cells expressing individual HLA class I alleles to define minimal epitope length and HLA restriction by stimulation of IFN-γ and TNF-α production and surface expression of CD107a. Using lymphocyte samples of 12 vaccine recipients, we defined 14 previously unreported optimal CD8+ T-cell HIV-1 epitopes and their four-digit HLA allele restriction (6 HLA-A, 7 HLA-B and 1 HLA-C alleles). Further 13 novel targets with incomplete information were revealed. The high rate of discovery of novel CD8+ T-cell effector epitopes warrants further epitope mining in recipients of the conserved-region vaccines in other populations and informs development of HIV-1/AIDS vaccines. ClinicalTrials.gov NCT01151319.

Human leukocyte antigen (HLA)-E binds epitopes derived from HLA-A, HLA-B, HLA-C and HLA-G signal peptides (SPs) and serves as a ligand for CD94/NKG2A and CD94/NKG2C receptors expressed on natural killer and T cell subsets. We show that among 16 common classical HLA class I SP variants, only 6 can be efficiently processed to generate epitopes that enable CD94/NKG2 engagement, which we term ‘functional SPs’. The single functional HLA-B SP, known as HLA-B/−21M, induced high HLA-E expression, but conferred the lowest receptor recognition. Consequently, HLA-B/−21M SP competes with other SPs for providing epitope to HLA-E and reduces overall recognition of target cells by CD94/NKG2A, calling for reassessment of previous disease models involving HLA-B/−21M. Genetic population data indicate a positive correlation between frequencies of functional SPs in humans and corresponding cytomegalovirus mimics, suggesting a means for viral escape from host responses. The systematic, quantitative approach described herein will facilitate development of prediction algorithms for accurately measuring the impact of CD94/NKG2–HLA-E interactions in disease resistance/susceptibility. Human leukocyte antigen (HLA)-E binds epitopes derived from HLA-A, HLA-B, HLA-C and HLA-G signal peptides (SPs) and serves as a ligand for CD94/NKG2A and CD94/NKG2C receptors. Carrington and colleagues provide comprehensive analysis of classical HLA class I SP variants and show that these can determine CD94/NKG2–HLA-E engagement.

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4 + T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3′ untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4 + T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression. Multiple genetic variants have been identified that influence the outcome of HIV infection. Carrington and colleagues investigate the mechanism of one of the strongest variants, rs1015164, and show that it influences expression of a lncRNA controlling CCR5 expression.

Fine definition of targeted CD8.sup.+ T-cell epitopes and their human leucocyte antigen (HLA) class I restriction informs iterative improvements of HIV-1 T-cell vaccine designs and may predict early vaccine success or failure. Here, lymphocytes from volunteers, who had received candidate HIVconsv vaccines expressing conserved sub-protein regions of HIV-1, were used to define the optimum-length target epitopes and their HLA restriction. In HIV-1-positive patients, CD8.sup.+ T-cell responses predominantly recognize immunodominant, but hypervariable and therefore less protective epitopes. The less variable, more protective epitopes in conserved regions are typically subdominant. Therefore, induction of strong responses to conserved regions by vaccination provides an opportunity to discover novel important epitopes. Cryopreserved lymphocytes from vaccine recipients were expanded by stimulation with 15-mer responder peptides for 10 days to establish short term-cell-line (STCL) effector cells. These were subjected to intracellular cytokine staining using serially truncated peptides and peptide-pulsed 721.221 cells expressing individual HLA class I alleles to define minimal epitope length and HLA restriction by stimulation of IFN-[gamma] and TNF-[alpha] production and surface expression of CD107a. Using lymphocyte samples of 12 vaccine recipients, we defined 14 previously unreported optimal CD8.sup.+ T-cell HIV-1 epitopes and their four-digit HLA allele restriction (6 HLA-A, 7 HLA-B and 1 HLA-C alleles). Further 13 novel targets with incomplete information were revealed. The high rate of discovery of novel CD8.sup.+ T-cell effector epitopes warrants further epitope mining in recipients of the conserved-region vaccines in other populations and informs development of HIV-1/AIDS vaccines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tight gas is an unconventional resource abundantly found in low-porosity, low-permeability sandstone reservoirs. Production can be significantly reduced due to water production during the development process. Therefore, it is necessary to predict water production during the logging phase to formulate development strategies for tight gas wells. This study analyzes the water production mechanism in tight sandstone reservoirs and identifies that the core of water production evaluation in the Shihezi Formation of the Linxing block is to clarify the pore permeability structure of tight sandstone and the type of intra-layer water. The primary challenge lies in the accurate characterization of bound water saturation. By integrating logging data with core experiments, a bound water saturation evaluation model based on grain size diameter and pore structure index was established, achieving a calculation accuracy of 92% for the multi-parameter-fitted bound water saturation. Then, based on the high-precision bound water saturation, a gas–water ratio prediction model for the first month of production, considering water saturation, grain size diameter, and fluid type, was established, improving the prediction accuracy to 87.7%. The bound water saturation evaluation and water production evaluation models in this study can achieve effective water production prediction in the early stage of production, providing theoretical support for the scientific development of tight gas in the Linxing block.

Maternal rectovaginal colonization with Group B Streptococcus (GBS) during labor is a prerequisite for neonatal early-onset GBS disease. Intrapartum antibiotic prophylaxis (IAP) has been proven to prevent GBS perinatal infection, while there are few studies on the evaluation of the effectiveness of different antibiotic prophylaxis regimens. This study aimed to assess the maternal rectovaginal GBS colonization status after IAP, antimicrobial susceptibility and maternal and neonatal outcomes among women administered different antibiotic prophylaxis regimens. A prospective study was conducted between June 2018 and June 2022. GBS carriers identified at 35–37 weeks of gestation were provided IAP (penicillin, cefazolin or clindamycin) at delivery based on the local protocol for GBS prevention. Rectovaginal samples were obtained from participants again after delivery. Antimicrobial susceptibility testing in GBS isolates was performed using the broth microdilution method. A total of 295 cases were included in this study. In the postpartum re-examination for GBS, the overall negative rectovaginal culture rate was 90.8% (268/295). Women who received cefazolin prophylaxis had the highest negative culture rate (95.2%, 197/207), which was followed by those who received penicillin (80.7%, 67/83) and clindamycin (80.0%, 4/5) (p = 0.001). All GBS isolates achieved sensitivity to penicillin and cefazolin, whereas resistance to clindamycin was shown in 21.4% of the strains. There were no significant differences in maternal and neonatal outcomes among the IAP groups. The use of IAP is highly effective in reducing the maternal rectovaginal GBS colonization. Cefazolin may offer equivalent efficacy and safety compared to standard penicillin prophylaxis.

The PLA/Rice straw fiber composites with various content ratios were prepared by using an internal mixer and a flatten press. The thermal properties, interface effect and mechanical performance of as-prepared PLA/Rice straw fiber composites were studied by mechanical performance measurement, TG, DSC and SEM technique. It was found that increasing the content of rice straw fiber leads to the decrease of the melting temperature while the improvement of the crystallinity of these composites. Introducing the rice straw fibers into PLA matrix does not result in any enhancement of mechanical property. However, the tensile strength of the composite increases as the content of rice straw fiber increases from 10% to 30%. The interface effect between fibers and PLA was obviously observed by SEM photo. It was thought such an issue could be improved by the addition of appropriate coupling agents into the composites.