LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection.

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10-2). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10-11-10-9) and African (p = 10-5-10-3) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement

Haboob Dust Storms and Motor Vehicle Collision-related Trauma in Phoenix, Arizona

Background: The Sonoran Desert region, encompassing most of southern Arizona, has an extreme climate that is famous for dust storms known as haboobs. These storms lead to decreased visibility and potentially hazardous driving conditions. In this study we evaluate the relationship between haboob events and emergency department (ED) visits due to motor vehicle collisions (MVCs) in Phoenix, Arizona.Methods: This study is a retrospective analysis of MVC-related trauma presentations to Phoenix, AZ, hospitals before and following haboob dust storms. These events were identified from 2009–2017 primarily using Phoenix International Airport weather data. De-identified trauma data were obtained from the Arizona Department of Health Services (ADHS) Arizona State Trauma Registry (ASTR) from seven trauma centers within a 10-mile radius of the airport. We compared MVC-related trauma using six- and 24-hour windows before and following the onset of haboob events.Results: There were 31,133 MVC-related trauma encounters included from 2009–2017 and 111 haboob events meeting meteorological criteria during that period. There was a 17% decrease in MVC-related ED encounters in the six hours following haboob onset compared to before onset (235 vs 283, P = 0.04), with proportionally more injuries among males (P < 0.001) and higher mortality (P = 0.02). There was no difference in frequency of presentations (P = 0.82), demographics, or outcomes among the 24-hour pre-and post-haboob groups.Conclusion: Haboob dust storms in Phoenix, Arizona, are associated with a decrease in MVC-related injuries during the six-hour period following storm onset, likely indicating the success of public safety messaging efforts. Males made up a higher proportion of those injured during the storms, suggesting a target for future interventions. Future public-targeted weather-safety initiatives should be accompanied more closely by monitoring and evaluation efforts to assess for effectiveness

Haboob Dust Storms and Motor Vehicle Collision-related Trauma in Phoenix, Arizona

Background: The Sonoran Desert region, encompassing most of southern Arizona, has an extreme climate that is famous for dust storms known as haboobs. These storms lead to decreased visibility and potentially hazardous driving conditions. In this study we evaluate the relationship between haboob events and emergency department (ED) visits due to motor vehicle collisions (MVCs) in Phoenix, Arizona. Methods: This study is a retrospective analysis of MVC-related trauma presentations to Phoenix, AZ, hospitals before and following haboob dust storms. These events were identified from 2009–2017 primarily using Phoenix International Airport weather data. De-identified trauma data were obtained from the Arizona Department of Health Services (ADHS) Arizona State Trauma Registry (ASTR) from seven trauma centers within a 10-mile radius of the airport. We compared MVC-related trauma using six- and 24-hour windows before and following the onset of haboob events. Results: There were 31,133 MVC-related trauma encounters included from 2009–2017 and 111 haboob events meeting meteorological criteria during that period. There was a 17% decrease in MVC-related ED encounters in the six hours following haboob onset compared to before onset (235 vs 283, P = 0.04), with proportionally more injuries among males ( P < 0.001) and higher mortality ( P = 0.02). There was no difference in frequency of presentations ( P = 0.82), demographics, or outcomes among the 24-hour pre-and post-haboob groups. Conclusion: Haboob dust storms in Phoenix, Arizona, are associated with a decrease in MVC-related injuries during the six-hour period following storm onset, likely indicating the success of public safety messaging efforts. Males made up a higher proportion of those injured during the storms, suggesting a target for future interventions. Future public-targeted weather-safety initiatives should be accompanied more closely by monitoring and evaluation efforts to assess for effectiveness

Spearman correlation between LILRB2 binding strength and mVL in HIV-1-infected individuals.

<p>Spearman correlation between LILRB2 binding strength and mVL in HIV-1-infected individuals.</p

Effect of LILRB2-HLA binding strength and individual class I alleles on viral control (controllers vs. non-controllers) in white patients.

<p>Logistic regression model with stepwise selection included all <i>HLA</i> class I alleles with phenotypic frequencies of >2% and one of the A, B, C or ABC binding scores at a time. The results are shown for the p<0.05 cut-off. The C binding score did not stay in the model. ORs for binding scores reflect a change of 0.1 units.</p>1<p>stayed in the model with the p<0.01 cut-off but not with the p<0.001 cut-off.</p>2<p>stayed in the model with the p<0.01 and p<0.001 cut-offs.</p

LILRB2-HLA binding score variations in 2900 white (A) and 1490 black (B) patients.

<p>A, B and C binding scores represent the sum of the binding scores for two alleles of the corresponding <i>HLA</i> class I locus. ABC binding score represents the sum of the locus-specific binding scores with the C scores counted at 1/10 level. Alleles with undefined scores were assigned the average of the scores for a given locus. Box and Whisker plots reflect median, the 25% and 75% percentiles and the minimum and maximum of all data.</p

LILRB2 binding strength and odds ratios for viral load control for individual <i>HLA-B</i> alleles.

<p>The data plotted includes only alleles with significant association (p<0.05) for white (A) and black (B) patients in a univariate analysis for each <i>HLA-B</i> allele. Spearman correlation coefficient and p values are indicated.</p

Impact of LILRB2-HLA interactions on functional properties of dendritic cells.

<p>(A) Fold changes in proliferative activities of allogeneic CD4⁺ T cells after exposure to MDDC treated with indicated HLA-A, -B or -C allotypes normalized to MDDC treated with negative beads (N. Bead), in the absence (white bars, n = 5, 8, 5 for HLA-A, -B, -C allotypes, respectively) or presence (gray bars, n = 5, 6, 5 for HLA-A, -B, -C allotypes, respectively) of siRNA-mediated downregulation of LILRB2 surface expression on MDDC. Significance was tested using one-way ANOVA followed by post-hoc analysis with the Tukey multiple comparison test, or using paired t-tests, as appropriate, (^▪p<0.05, ^Xp<0.01, *p<0.001). (B): Spearman correlation between proliferative activities of allogeneic CD4⁺ T cells after incubation with MDDC treated with indicated HLA-A, -B and -C allotypes and corresponding LILRB2-HLA binding scores. (C): Spearman correlation between the ratios of MDDC function in the presence or absence of siRNA-mediated LILRB2 downregulation, and corresponding LILRB2-HLA-A, -B, -C binding scores.</p

Effect of the LILRB2-HLA binding strength and individual class I alleles on viral control in black patients.

<p>The analysis was similar to the one described in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004196#pgen-1004196-t003" target="_blank">Table 3</a>. The A and C scores did not stay in the model.</p>1<p>stayed in the model with the p<0.01 and p<0.001 cut-offs.</p>2<p>stayed in the model with the p<0.01 cut-off but not with the p<0.001 cut-off.</p